bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes and pancreatic cancer risk in a multiracial cohort
Authors: Conway Rebecca B. N. , Hudson Alana G. , Munro Heather , Fu David , McClain Donald A. , Blot William J.
Published: October 2023

Aims

To determine the relationship of diabetes with pancreatic cancer incidence among African American and Whites of similar socio‐economic status.

Methods

Using the Southern Community Cohort Study, we conducted a follow‐up during 2002–2015 of pancreatic cancer incidence of 73,378 mostly low‐income participants aged 40–79 years; 15,913 reported diabetes at baseline. Multivariable Cox analysis controlling for sex, family history of pancreatic cancer, BMI, smoking status, alcohol consumption, education, income and other important covariates, and with age as the timescale was used.

Results

Totally, 265 incident pancreatic cancer cases were observed. Pancreatic cancer risk was increased among those with diabetes (HR 1.54, CI 1.16–2.05), with similar increases among African Americans (HR 1.51, CI 1.08–2.11) and Whites (HR 1.78, CI 1.00–3.16). No trend in risk was observed for diabetes duration among those with diabetes, with HRs of 1.39 (0.91–2.11), 2.31 (1.51–3.54) and 1.23 (0.80–1.89) for <5, 5–9 and 10+ years duration, respectively. African Americans were at increased risk of pancreatic cancer (HR = 1.40, 95% CI 1.05–1.87), which persisted after adjusting for diabetes (HR 1.36, CI 1.02–1.81). The effect sizes for other pancreatic cancer risk factors with pancreatic cancer were similar by diabetes status, although a stronger association with low BMI was evident among those with diabetes.

Conclusions

Diabetes increases pancreatic cancer risk similarly among African Americans and Whites in this Southern U.S. cohort.
Differential effect of interventions in patients with prediabetes stratified by a machine learning‐based diabetes progression prediction model
Authors: Zou Xiantong , Luo Yingying , Huang Qi , Zhu Zhanxing , Li Yufeng , Zhang Xiuying , Zhou Xianghai , Ji Linong
Published: October 2023

Aim

To investigate whether stratifying participants with prediabetes according to their diabetes progression risks (PR) could affect their responses to interventions.

Methods

We developed a machine learning‐based model to predict the 1‐year diabetes PR (ML‐PR) with the least predictors. The model was developed and internally validated in participants with prediabetes in the Pinggu Study (a prospective population‐based survey in suburban Beijing; n = 622). Patients from the Beijing Prediabetes Reversion Program cohort (a multicentre randomized control trial to evaluate the efficacy of lifestyle and/or pioglitazone on prediabetes reversion; n = 1936) were stratified to low‐, medium‐ and high‐risk groups using ML‐PR. Different effect of four interventions within subgroups on prediabetes reversal and diabetes progression was assessed.

Results

Using least predictors including fasting plasma glucose, 2‐h postprandial glucose after 75 g glucose administration, glycated haemoglobin, high‐density lipoprotein cholesterol and triglycerides, and the ML algorithm XGBoost, ML‐PR successfully predicted the 1‐year progression of participants with prediabetes in the Pinggu study [internal area under the curve of the receiver operating characteristic curve 0.80 (0.72–0.89)] and Beijing Prediabetes Reversion Program [external area under the curve of the receiver operating characteristic curve 0.80 (0.74–0.86)]. In the high‐risk group pioglitazone plus intensive lifestyle therapy significantly reduced diabetes progression by about 50% at year l and the end of the trial in the high‐risk group compared with conventional lifestyle therapy with placebo. In the medium‐ or low‐risk group, intensified lifestyle therapy, pioglitazone or their combination did not show any benefit on diabetes progression and prediabetes reversion.

Conclusions

This study suggests personalized treatment for prediabetes according to their PR is necessary. ML‐PR model with simple clinical variables may facilitate personal treatment strategies in participants with prediabetes.
Designers in the Hands of a Passionate Leader
Authors: Fain Lee
Published: October 2023

Are you thinking of bringing a design department into your business? Do you deal on a regular basis with design consultants? Here are some ideas for making that relationship a productive one.

How to work with creatives in a way that brings mutual satisfaction—and value—to both the business manager and the designer.
Q&A
Authors: Quint Eric
Published: October 2023

Only around 10 percent of Fortune 100 companies call design an executive priority, and only a handful of those have installed a chief design officer. As CDO for 3M Corp., Eric Quint has plenty to say about leadership, investment, and “creating the oxygen” for a long‐term creative transformation.
Antemortem diagnosis of renal haemangiosarcoma in a Hanoverian gelding
Authors: Williams Zoë J. , French Stephanie , Hollinger Charlotte , Pease Anthony P. , Schott Harold C.
Published: October 2023

Haemangiosarcoma is an uncommon neoplasm in horses that is rarely diagnosed antemortem. A 27‐year‐old Hanoverian gelding was presented to the Michigan State University Veterinary Medical Center for evaluation of lethargy, weight loss, stiffness and more recent colic signs. At presentation, the gelding was alert with mild tachycardia (60 beats/min). Other physical findings were normal except for a mass detected in the area of the left kidney on rectal palpation. Laboratory analyses revealed anaemia, hypoproteinaemia, hypoalbuminaemia and hyperbilirubinaemia consistent with haemorrhage and haemolysis. Transabdominal ultrasonography revealed the left kidney to be an enlarged heterogenous mass, and numerous 1–2 cm diameter hyperechoic nodules (without shadow artefacts) were imaged within the right kidney. After inconclusive results were returned on percutaneous biopsy of the left renal mass, a right renal biopsy yielded a diagnosis of haemangiosarcoma. Palliative care was initiated with dexamethasone, but 19 days after hospital discharge the gelding became recumbent, and humane euthanasia was performed. Necropsy examination confirmed disseminated haemangiosarcoma including both kidneys, adrenal glands, spleen, heart and lungs with the largest neoplasm in the left kidney.
Evaluation of glutaraldehyde coagulation test and colostrum BRIX refractometer compared with SNAP foal IgG test in neonatal foals
Authors: Kasap Sevim , Babaeski Serdar , Yildirim Kubra Nur , Orman Abdulkadir , Temizel Ethem Mutlu , Kennerman Engin
Published: October 2023

Background

Prompt diagnosis of passive transfer failure in the neonatal period is important for early treatment.

Objectives

To compare the diagnostic performance of serum glutaraldehyde coagulation test (GCT) and colostrum BRIX% for failure to transfer passive immunity (FTPI) diagnosis with the results of SNAP foal test and to evaluate the results of serum GCT and colostrum BRIX% measurements in foals with diarrhoea in the 0–1 month period.

Study design

In vitro experiments.

Methods

Excess serum and colostrum (n: 298) from samples collected from newborn foals and their dams for clinical purposes were used. Foals were classified as FTPI positive (IgG < 8 g/L) or negative (IgG ≥ 8 g/L) using the SNAP foal test. We compared the sensitivity and specificity of serum GCT and colostrum BRIX % for diagnosing FTPI in all foals and in the sub‐group of foals which developed diarrhoea within the first month of life was noted. The relationships between the results of the serum GCT and colostrum BRIX% and diarrhoea in foals with and without FTPI were evaluated.

Results

Serum GCT and colostrum BRIX % were statistically significantly different (p < 0.05) between the foals without FTPI and with FTPI classified according to the SNAP test. Using a cut‐off value for serum GCT of >10, sensitivity was 100% (95% CI 92.9%–100%) and specificity 100% (98.3%–100%) while with a cut‐off value of ≤24, with colostrum BRIX% of ≤24 sensitivity was 92% (80.9%–97.8%), and specificity was 98% (95.3–99.3). In the sub‐group of foals without FTPI using a colostrum BRIX% cut‐off value of ≤26 the sensitivity for prediction of diarrhoea in the 0–1 month period was only 72.4% (52.8–87.3, p < 0.001) with specificity 54.3% (47.6–61.1) but the test performance was not robust (ROC AUC 0.61).

Main limitations

The number of repeated measurements in the evaluation of serum GCT, and colostrum BRIX% was low. More clinical problems could be examined.

Conclusions

The serum GCT, and colostrum BRIX%, both economical and practical to use in the field, gave results comparable with the SNAP foal IgG test. The ability to accurately predict diarrhoea in the first month of life with these tests was limited.
RETRACTED: Effects of tourniquet on surgical site wound infection and pain after total knee arthroplasty: A meta‐analysis
Authors: Lin Zhengwu , Chen Te , Chen Guofu , Pan Wenjun , Xu Wei
Published: October 2023

The application of a tourniquet (TNQ) for haemostasis in total knee arthroplasty (TKA) is controversial and lacking systematic evaluation. This meta‐analysis assessed relevant international data to quantitatively evaluate the implications of using TNQ in TKA, further guide clinical diagnosis and treatment, and improve postoperative outcomes. A comprehensive computerised search of PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, VIP, and Wanfang databases was conducted to retrieve randomised controlled trials on the application of TNQ in TKA published from database inception to August 2023. The included data, ultimately comprising 1482 patients in 16 studies, were collated and subjected to meta‐analysis using Stata 17.0 software. The results showed that the use of TNQ during TKA led to significantly higher rates of postoperative surgical site wound infection (3.96% vs. 1.79%, odds ratio: 2.15, 95% confidence intervals [CIs]: 1.11–4.16, p = 0.023) and wound pain scores on the first (standardised mean difference [SMD]: 0.65, 95% CI: 0.35–0.94, p < 0.001), second (SMD: 0.66, 95% CI: 0.01–1.31, p = 0.045), and third (SMD: 0.68, 95% CI: 0.31–1.05, pP < 0.001) day after the procedure. In conclusion, the application of TNQ in TKA increases the risk of postoperative surgical site wound infection and worsens short‐term postoperative wound pain; therefore, TNQ should be used sparingly during TKA, or its use should be decided in conjunction with the relevant clinical indications and the surgeon's experience.
Francis Fukuyama: Democracy Needs Elites
Authors: Görlach Alexander , Fukuyama Francis
Published: October 2023

“Populism exists because institutions are elite‐driven,” but democracies don't work well without elites, says the acclaimed author of The End of History.
A Mutiny Against Modernizing Elites Has Erupted In The West
Authors: Mishra Pankaj
Published: October 2023

In a conversation with NPQ, the Indian author discusses his book, Age of Anger, and what's propelled a backlash against the cosmopolitan caste.
On explicit birational geometry for minimal n$n$‐folds of canonical dimension n−1$n-1$
Authors: Chen Meng , Esser Louis , Wang Chengxi
Published: October 2023

Let be any integer. We study the optimal lower bound of the canonical volume and the optimal upper bound of the canonical stability index for minimal projective ‐folds of general type, which are canonically fibered by ‐folds (). The results for are known to experts. In this article, we compute sharp bounds for and give some characterization of optimal examples. The machinery introduced is applicable to all canonical dimensions .
Cost-effectiveness of a decentralized care model for managing multi-drug-resistant tuberculosis in low- and middle-income countries: a systematic review protocol
Authors: Mahapatra Biswajit , Bhattacharya Paramita , Karuveettil Vineetha , John Denny , Khatoon Sajda , Mukherjee Nirmalya , Jankiram Chandrashekar
Published: October 2023

Objective:

The purpose of this systematic review is to assess the available economic evidence of a decentralized care model compared to a centralized model for treating multi-drug-resistant tuberculosis (MDR-TB) in low- and middle-income countries (LMICs).

Introduction:

Diseases that affect physiological health create a burden on human livelihoods and the economy. There is a lack of studies examining the economic evaluation of MDR-TB across different countries. A preliminary search identified no published or ongoing reviews on MDR-TB in LMICs.

Inclusion criteria:

Studies will be eligible if they include both patients receiving centralized care (ie, care provided by specialist centers through inpatient or outpatient services) and patients receiving decentralized care (ie, care provided by grassroots community workers in peripheral facilities or in the patients' residence) for MDR-TB in LMICs. Eligible studies will report economic evaluations of treatment for MDR-TB.

Methods:

A preliminary search of MEDLINE (PubMed) was undertaken using MeSH terms, such as MDR-TB, economic evaluation, therapeutics, LMICs. Two reviewers will independently screen the titles, abstracts, and full text against the inclusion criteria. Disagreements will be resolved through discussion or with a third reviewer. The JBI checklist for economic evaluations will be utilized to evaluate the methodological quality. Data will be extracted using a modified JBI data extraction form for economic evaluations. The Dominance Ranking Matrix, developed by JBI for economic evaluations, will be used to summarize and compare the results of different types of economic evaluations (cost-effectiveness, cost-benefit analysis, cost-utility analysis, or cost-minimization analysis). Cost per quality-adjusted life year gained and cost per disability-adjusted life year averted will be measures for economic evaluation. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach will be used to assess the certainty of economic evidence.

Review registration:

PROSPERO CRD42022368696
Manipulación del resultado contable en Latinoamérica: evidencias de la corrupción organizacional
Authors: Usme Suárez Wilson Alexis , Ospina Delgado Julieth E. , Van Hemmen Stefan Felix
Published: October 2023

Este artículo examina si existe evidencia del problema de manipulación del resultado en Latinoamérica, así como la intención de información (pérdidas o ganancias) de las organizaciones en la región. Para este cometido, se recurre a la metodología de análisis gráfico y estadístico de distribuciones, que da señales sobre el problema. Este análisis se realiza en una muestra de compañías cotizadas de 11 países de Latinoamérica. Los resultados sugieren que, en general, la manipulación del resultado en Latinoamérica se da para informar sobre pequeñas pérdidas en el resultado operativo y pequeñas ganancias en el resultado neto. En particular, se encuentra evidencia estadística de manipulación del resultado a nivel país para Chile, Ecuador, México, Perú y Venezuela.
Identification of proteoforms of short open reading frame-encoded peptides in
Blautia producta
under different cultivation conditions
Authors: Genth Jerome , Schäfer Kathrin , Cassidy Liam , Graspeuntner Simon , Rupp Jan , Tholey Andreas
Published: October 2023

Short open reading frames (sORF) have the potential to encode small proteins, sORF-encoded peptides (SEP), which are less than or equal to 100 amino acids in length. These SEP have been associated with various physiological processes and are known for their potential roles in modulating immune responses, signaling pathways, and cellular functions. Using bottom-up and top-down proteomics, we identified 45 novel and formerly reported SEP under different growth conditions and stress exposure in single cultures of
Blautia producta
that plays a central role in mediating colonization resistance and dampening inflammation in the human gut microbiome. Top-down analysis improved identification confidence and allowed the detection of a number of full-length and N- or C-terminal truncated proteoforms of the SEP and of proteoforms carrying post-translational modifications such as disulfides, which provides hints for a wide functional potential of these molecules. The identification of the SEP in single cultures of this bacterium shows that, in contrast to previous results, the biosynthesis of specific SEP is not restricted to direct bacterial interactions within the microbiome but is dependent on growth and environmental conditions during cultivation.

IMPORTANCE

The identification of short open reading frame-encoded peptides (SEP) and different proteoforms in single cultures of gut microbes offers new insights into a largely neglected part of the microbial proteome landscape. This is of particular importance as SEP provide various predicted functions, such as acting as antimicrobial peptides, maintaining cell homeostasis under stress conditions, or even contributing to the virulence pattern. They are, thus, taking a poorly understood role in structure and function of microbial networks in the human body. A better understanding of SEP in the context of human health requires a precise understanding of the abundance of SEP both in commensal microbes as well as pathogens. For the gut beneficial
B. producta
, we demonstrate the importance of specific environmental conditions for biosynthesis of SEP expanding previous findings about their role in microbial interactions.
Note on $$T{\bar{T}}$$ deformed matrix models and JT supergravity duals
Authors: He Song , Ouyang Hao , Sun Yuan
Published: October 2023

In this work we calculate the partition functions of $${\mathcal {N}}=1$$

N
=
1

type 0A and 0B JT supergravity (SJT) on 2D surfaces of arbitrary genus with multiple finite cut-off boundaries, based on the $$T{\bar{T}}$$

T

T

¯

deformed super-Schwarzian theories. In terms of SJT/matrix model duality, we compute the corresponding correlation functions in the $$T{\bar{T}}$$

T

T

¯

deformed matrix model side by using topological recursion relations as well as the transformation properties of topological recursion relations under $$T{\bar{T}}$$

T

T

¯

deformation. We check that the partition functions finite cut-off 0A and 0B SJT on generic 2D surfaces match the associated correlation functions in $$T{\bar{T}}$$

T

T

¯

deformed matrix models respectively.
The Haptic Intensity Order Illusion Is Caused by Amplitude Changes
Authors: Makarov Ivan , Stefánsson Thors Snorri Steinn , Ævarsson Elvar Atli , Jörgensson Finnur Kári Pind , Yeganeh Nashmin , Kristjánsson Árni , Unnthorsson Runar
Published: October 2023

When two brief vibrotactile stimulations are sequentially applied to observers’ lower back, there is systematic mislocalization of the stimulation: if the second stimulation is of higher intensity than the first one, observers tend to respond that the second stimulation was above the first one, and vice versa when weak intensity stimulation follows a strong one. This haptic mislocalization effect has been called the
intensity order illusion
. In the original demonstration of the illusion, frequency and amplitude of the stimulation were inextricably linked so that changes in amplitude also resulted in changes in frequency. It is therefore unknown whether the illusion is caused by changes in frequency, amplitude or both. To test this, we performed a multifactorial experiment, where we used L5 actuators that allow independent manipulation of frequency and amplitude. This approach enabled us to investigate the effects of stimulus amplitude, frequency and location, and to assess any potential interactions among these factors. We report four main findings: (1) we were able to replicate the intensity order illusion with the L5 tactors; (2) the illusion mainly occurred in the upwards direction, or in other words, when strong stimulation following a weaker one occurred above or in the same location as the first stimulation; (3) the illusion did not occur when similar stimulation patterns were applied in the horizontal direction; and (4) the illusion was solely due to changes in amplitude, whereas changes in frequency (100 Hz vs 200 Hz) had no effect.
Switching Constrained Online Convex Optimization with Predictions and Feedback Delays
Authors: Pan Weici , Liu Zhenhua
Published: October 2023

In various applications such as smart grids, the online player is allowed a limited number of switches among decisions. Additionally, real-world scenarios often involve feedback delays or access to near-future predictions. Motivated by this, we study Online Convex Optimization with a switching limit, incorporating feedback delays and predictions. In this extended abstract, we established a near-optimal regret of O(T/S) for delayed feedbacks and a bound of O(T/S - t ) for predictions of t rounds even though the player is only allowed to move at most S times, in expectation, across T rounds. We developed an algorithm which achieves the bounds in both cases and still works when there are both delays and predictions.
The stationary distribution of the redundancy-d model with random order of service
Authors: Anton E. , Gardner K.
Published: October 2023

Redundancy has gained considerable attention as a dispatching paradigm that promises the potential for significant response time improvements, see [4, 6] and the references therein. The premise of redundancy is that upon a job's arrival, multiple copies of the job are dispatched to different servers. A job's class is defined by the set of servers to which its copies are dispatched, and there is a bipartite graph specifying the relationships between job classes and servers. A job is considered complete, and departs from the system, as soon as any one of its copies has completed service. The additional copies of a job are removed either (i) when the first copy enters service, known as the cancel-onstart (c.o.s.) model, or (ii) when the first copy completes service, known as the cancel-on-complete (c.o.c.) model. In both models, redundancy has the potential to significantly reduce response time by exploiting the variability of queue lengths and server capacities.
Insensitivity for Loss Systems with Compatibilities
Authors: Xie Runhan , Gardner Kristen , Righter Rhonda
Published: October 2023

In the study of queueing systems, we are often interested in finding the stationary distribution of the system state, which in turn can be used to compute various performance measures of interest. Under the assumption that the arrival process is Poisson and the service time distribution is exponential, many queueing systems have elegant productform stationary distributions. However, the exponentiality assumption is often unrealistic. Although relaxing this assumption typically makes the analysis of the stationary distribution less tractable, a number of queueing systems are insensitive to the service time distribution, meaning that they have the same stationary distribution under all service time distributions. Below we describe several examples.
Optimal Rate-Matrix Pruning For Heterogeneous Systems
Authors: Zhao Zhisheng , Mukherjee Debankur
Published: October 2023

We consider large-scale load balancing systems where processing time distribution of tasks depend on both task and server types. We analyze the system in the asymptotic regime where both the number of task and server types tend proportionally to infinity. In such heterogeneous setting, popular policies like Join Fastest Idle Queue (JFIQ), Join Fastest Shortest Queue (JFSQ) are known to perform poorly and they even shrink the stability region. Moreover, to the best of our knowledge, in this setup, finding a scalable policy with provable performance guarantee has been an open question prior to this work. In this paper, we propose and analyze two asymptotically delay-optimal dynamic load balancing policies: (a) one that efficiently reserves the processing capacity of each server for "good" tasks and route tasks under the Join Idle Queue policy; and (b) a speed-priority policy that increases the probability of servers processing tasks at a high speed. Leveraging a framework inspired by the graphon literature and using the mean-field method and stochastic coupling arguments, we prove that both policies above achieve asymptotic zero queueing, whereby the probability that a typical task is assigned to an idle server tends to 1 as the system scales.
What is an Optimal Policy in Time-Average MDP?
Authors: Gast Nicolas , Gaujal Bruno , Khun Kimang
Published: October 2023

This paper discusses the notion of optimality for time-average MDPs. We argue that while most authors claim to use the "average reward" criteria, the notion that is implicitly used is in fact the notion of what we call Bellman optimality. We show that it does not coincide with other existing notions of optimality, like gain-optimality and bias-optimality but has strong connection with canonical-policies (policies that are optimal for any finite horizons) as well as value iteration and policy iterations algorithms.
Performance of the Gittins Policy in the G/G/1 and G/G/k, With and Without Setup Times
Authors: Hong Yige , Scully Ziv
Published: October 2023

We consider the classic problem of preemptively scheduling jobs of unknown size (a.k.a. service time) in a queue to minimize mean number-in-system, or equivalently mean response time (a.k.a. sojourn time). We know how to solve this problem in an M/G/1, provided the job size distribution is known to the scheduler. In this case, the optimal policy is the Gittins policy (a.k.a. Gittins index policy) [1].
Markov Decision Process Framework for Control-Based Reinforcement Learning
Authors: Lu Yingdong , Squillante Mark S. , Wah Wu Chai
Published: October 2023

For many years, reinforcement learning (RL) has proven to be very successful in solving a wide variety of learning and decision making under uncertainty (DMuU) problems, including those related to game playing and robotic control. Many different RL approaches, with varying levels of success, have been developed to address these problems.
Teaching Software Performance Evaluation to Undergrads: Lessons Learned and Challenges
Authors: Krishnamurthy Diwakar
Published: October 2023

Recent high-profile performance-related outages and problems in industry clearly establish the importance of imparting performance evaluation skills to students at the undergrad level.
Tackling Deployability Challenges in ML-Powered Networks
Authors: Rotman Noga H.
Published: October 2023

Following the success of Machine Learning (ML) in various fields such as natural language processing, computer vision and computational biology, there has been a growing interest in incorporating ML into the networking domain [5, 6, 14, 4, 9]. Today, ML-based algorithms for prominent networking problems such as congestion control, resource management and routing, perform very well when their training environment is faithful to the operational environment, achieving state-of-the-art results when compared to traditional algorithms. However, the adaptation of these algorithms to function in production environments has not been straightforward, as real-world networks may differ greatly from the data used for training, leading to a drop in performance when unleashed into the wild.
Data from LncRNA AGPG Confers Endocrine Resistance in Breast Cancer by Promoting E2F1 Activity
Authors: Yu Shiyi , Wang Ying , Gong Xue , Fan Zhehao , Wang Zheng , Liang Zhengyan , Wu Rui , Cao Binjie , Wang Ning , Bi Caili , Lv Dan , Sun Haibo
Published: October 2023

Abstract
Resistance to endocrine therapy represents a major concern for patients with estrogen receptor α–positive (ERα+) breast cancer. Endocrine therapy resistance is commonly mediated by activated E2F signaling. A better understanding of the mechanisms governing E2F1 activity in resistant cells could reveal strategies for overcoming resistance. Here, we identified the long noncoding RNA (lncRNA) actin gamma 1 pseudogene 25 (AGPG) as a regulator of E2F1 activity in endocrine-resistant breast cancer. Expression of AGPG was increased in endocrine-resistant breast cancer cells, which was driven by epigenomic activation of an enhancer. AGPG was also abnormally upregulated in patient breast tumors, especially in the luminal B subtype, and high AGPG expression was associated with poor survival of patients with ERα+ breast cancer receiving endocrine therapy. The upregulation of AGPG mediated resistance to endocrine therapy and cyclin-dependent kinase 4/6 inhibition in breast cancer cells. Mechanistically, AGPG physically interacted with PURα, thus releasing E2F1 from PURα and leading to E2F1 signaling activation in ERα+ breast cancer cells. In patients with breast cancer, E2F1 target genes were positively and negatively correlated with expression of AGPG and PURα, respectively. Coadministration of chemically modified AGPG siRNA and tamoxifen strongly suppressed tumor growth in endocrine-resistant cell line–derived xenografts. Together, these results demonstrate that AGPG can drive endocrine therapy resistance and indicate that it is a promising biomarker and potential therapeutic target in breast cancer.
Significance:
Blockade of formation of the PURα/E2F1 complex by lncRNA AGPG activates E2F1 and promotes endocrine resistance, providing potential strategies for combatting endocrine-resistant breast cancer.
To Tip or Not to Tip: A New Combination for Precision Medicine in Head and Neck Cancer
Authors: Lee Rex H. , Johnson Daniel E. , Grandis Jennifer R.
Published: October 2023

Meaningful advances in targeted therapy for head and neck squamous cell carcinoma (HNSCC) have been hampered by limited availability of robust preclinical models for translational research. Using an impressive array of in vitro and in vivo preclinical HNSCC models, Smith and colleagues demonstrated the efficacy of alpelisib and tipifarnib combination therapy through sustained mTOR inhibition in PIK3CA/HRAS-dysregulated HNSCC, including preliminary evidence of robust antitumor activity in a patient enrolled in a precision medicine trial. This study in this issue of Cancer Research illustrates the value of preclinical avatars for informing biomarker-driven clinical trials to advance precision medicine in HNSCC and other cancers.

See related article by Smith et al., p. 3252
Data from A Phase II Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder
Authors: Li Roger , Sexton Wade J. , Dhillon Jasreman , Berglund Anders , Naidu Shreyas , Borjas Gustavo , Rose Kyle , Kim Youngchul , Wang Xuefeng , Conejo-Garcia Jose R. , Jain Rohit K. , Poch Michael A. , Spiess Philippe E. , Pow-Sang Julio , Gilbert Scott M. , Zhang Jingsong
Published: October 2023

AbstractPurpose:
Immune checkpoint blockade holds promise for treating bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). In this phase II study, we investigated the safety and efficacy of durvalumab, a human IgG1 monoclonal antibody, against BCG-unresponsive carcinoma in situ (CIS).
Patients and Methods:
Patients with BCG-unresponsive CIS-containing NMIBC received durvalumab IV at 1,500 mg every 4 weeks for up to 12 months. The primary endpoint was complete response (CR) rate at month 6, defined by negative cystoscopy, urine cytology, and absence of high-grade recurrence on bladder mapping biopsy. The null hypothesis specified a CR rate of 18% and alternative hypothesis of 40%. According to the Simon two-stage design, if ≤3/13 patients achieved CR during stage 1, the trial is stopped due to futility.
Results:
Between March 8, 2017, and January 24, 2020, 17 patients were accrued whereas 4 withdrew from study treatment after bladder biopsy at month 3 was positive for CIS. Two of 17 (12%) achieved a CR at month 6, with duration of response of 10 and 18 months, respectively. A single grade 3 lipase elevation was attributed to durvalumab, and immune-related adverse events were observed in 7/17 (41%) patients. Only 1/17 patients had high programmed death-ligand 1 expression pretreatment. On RNA sequencing, complement activation genes were elevated posttreatment, along with enrichment of tumor-associated macrophage signature.
Conclusions:
Durvalumab monotherapy conferred minimal efficacy in treating BCG-unresponsive CIS of the bladder, with 6-month CR of 12%. Complement activation is a potential mechanism behind treatment resistance.
Data from A Phase II Study of Optimized Individualized Adaptive Radiation Therapy for Hepatocellular Carcinoma
Authors: Herr Daniel J. , Wang Chang , Mendiratta-Lala Mishal , Matuszak Martha , Mayo Charles S. , Cao Yue , Parikh Neehar D. , Ten Haken Randy , Owen Dawn , Evans Joseph R. , Stanescu Teodor , Yan Michael , Dawson Laura A. , Schipper Matthew , Lawrence Theodore S. , Cuneo Kyle C.
Published: October 2023

Abstract
Purpose: We hypothesized that optimizing the utility of stereotactic body radiation therapy (SBRT) based on the individual patient’s probability for tumor control and risk of liver injury would decrease toxicity without sacrificing local control in patients with impaired liver function or tumors not amenable to thermal ablation. Methods: Patients with Child-Pugh (CP) A to B7 liver function with aggregate tumor size >3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an IRB approved phase II clinical trial to undergo SBRT with baseline and mid-treatment dose optimization using a quantitative, individualized utility-based analysis. Primary endpoints were change in CP score of ≥2 points within 6 months and local control. Protocol-treated patients were compared with patients receiving conventional SBRT at another cancer center using overlap weighting. Results: 56 patients with 80 treated tumors were analyzed with a median follow-up of 11.2 months. Two-year cumulative incidence of local progression was 6.4% (95% CI [2.4 – 13.4]). 21% of patients experienced treatment-related toxicity within 6 months, which is similar to the rate for SBRT in patients with CP A liver function. An analysis using overlap weighting revealed similar local control (HR 0.69, 95% CI [0.25-1.91], p = 0.48) and decreased toxicity (OR 0.26, 95% CI [0.07 – 0.99], p = 0.048) compared to conventional SBRT. Conclusion: Treatment of individuals with impaired liver function or tumors not amenable to thermal ablation with a treatment paradigm designed to optimize utility may decrease treatment-related toxicity while maintaining tumor control.
Data from Neoadjuvant Cabazitaxel Plus Abiraterone/Leuprolide Acetate in High-Risk Prostate Cancer Patients: ACDC-RP Phase II Trial
Authors: Fleshner Neil E. , Sayyid Rashid K. , Hansen Aaron R. , Chin Joseph L. K. , Fernandes Ricardo , Winquist Eric , van der Kwast Theodorus , Sweet Joan , Lajkosz Katherine , Kenk Miran , Hersey Karen , Veloso Rosette , Berlin Doron , Herrera-Caceres Jaime O. , Sridhar Srikala , Moussa Madeleine , Finelli Antonio , Hamilton Robert J. , Kulkarni Girish S. , Zlotta Alexandre R. , Joshua Anthony M.
Published: October 2023

Abstract
Purpose: Early treatment intensification with neoadjuvant therapy may improve outcomes in high-risk, localized prostate cancer (PCa) patients treated with radical prostatectomy (RP). Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to RP in localized, high-risk PCa patients. Patients and Methods: This open-label, multicenter, phase II trial randomized men with clinically localized, D’Amico high-risk PCa to neoadjuvant abiraterone acetate (1000mg/day) and leuprolide acetate (22.5mg every three months) with or without cabazitaxel (25mg/m2) prior to RP. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile. Results: The per-protocol population consisted of 70 patients (Cabazitaxel arm [Arm A]: 37, No cabazitaxel arm [Arm B]: 33). Median patient age and prostate-specific antigen levels were 63.5 years (IQR:58.0-68.0) and 21.9 ng/ml (IQR:14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in Arms A and B, respectively (p=0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in Arms A and B, respectively (p=0.66). Patients with ≤25% total biopsy cores positive had increased odds of pCR/MRD (p=0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% versus 62.0%, p=0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (p=0.078). Conclusion: Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to RP did not improve pCR/MRD in clinically localized, high-risk PCa.
Data from Comprehensive analysis of tumor microenvironment reveals prognostic ceRNA network related to immune infiltration in sarcoma
Authors: Leng Dongliang , Yang Ziyi , Sun Heng , Song Chengcheng , Huang Chen , Ip Ka U. , Chen Guokai , Deng Chu-Xia , Zhang Xiaohua Douglas. , Zhao Qi
Published: October 2023

Abstract
Purpose:Sarcoma (SARC) is the second most common solid tumor type in children and adolescents. The high level of tumor heterogeneity as well as aggressive behavior of SARCs bring serious difficulties to developing effective therapeutic strategies for clinical application. Therefore, it’s of great importance to identify accurate biomarkers for early detection and prognostic prediction of SARCs. Experimental Design:In this study, we characterized three subtypes of SARCs based on tumor immune infiltration levels (TIILs), and constructed a prognosis-related competing endogenous RNA (ceRNA) network to investigate molecular regulations in the sarcoma tumor microenvironment (TME). We further built a subnetwork consisting of mRNAs and lncRNAs which are targets of key miRNAs and strongly correlated with each other in the ceRNA network. After validation using public data and experiments in vivo and in vitro, we deeply dug the biological role of the miRNAs and lncRNAs in a subnetwork and their impact on TME. Results:Altogether, 5 miRNAs (hsa-mir-125b-2, hsa-mir-135a-1, hsa-mir92a-2, hsa-mir-181a-2, and hsa-mir-214), 3 lncRNAs (LINC00641, LINC01146, and LINC00892), and 10 mRNAs (AGO2, CXCL10, CD86, CASP1, IKZF1, CD27, CD247, CD69, CCR2, and CSF2RB) in the subnetwork were identified as vital regulators to shape the TME. Based on the systematic network, we identified that Trichostatin A, a pan-HDAC inhibitor, could potentially regulate the TME of sarcoma thereby inhibiting the tumor growth. Conclusions:Our study identifies a ceRNA network as promising biomarker for SARC. This system provides a more comprehensive understanding and a novel perspective of how ceRNAs are involving in shaping sarcoma TME.
Data from First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma
Authors: Hamilton Erika P. , Wang Judy S. , Oza Amit M. , Patel Manish R. , Ulahannan Susanna V. , Bauer Todd , Karlix Janet L. , Zeron-Medina Jorge , Fabbri Giulia , Marco-Casanova Paola , Moorthy Ganesh , Hattersley Maureen M. , Littlewood Gillian M. , Mitchell Patrick , Saeh Jamal , Pouliot Gayle P. , Moore Kathleen N.
Published: October 2023

Abstract
AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase II doses (RP2D) were AZD5153 30 mg once daily or 15 mg twice daily (monotherapy) and 10 mg once daily (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAE) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.
Data from Examining the Barriers and Opportunities for Human Papillomavirus Vaccine Delivery in Cancer Care Settings: A Mixed-Methods Study
Authors: Garcia Melany A. , Schlecht Nicolas F. , Rokitka Denise A. , Attwood Kristopher M. , Rodriguez Elisa M.
Published: October 2023

Abstract
Although pediatric, adolescent, and young adult (PAYA) cancer survivors are at increased risks for secondary cancers, their HPV vaccine uptake rates are poor. Therefore, we conducted a mixed-methods study to identify the barriers and opportunities for HPV vaccine delivery among PAYA cancer care providers. We distributed a semistructured questionnaire to a professional organization comprised of PAYA oncology and hematology healthcare providers between April and July 2022. Questionnaire measures included demographic and practice characteristics, HPV vaccine knowledge, willingness, barriers, opportunities, and roles for HPV vaccine delivery. Descriptive characteristics were generated for quantitative data, and content analysis was used to identify themes. A total of 49 providers responded to our survey. A majority were female (68%) and non-Hispanic white (74%). Approximately 76% were oncology or hematology physicians, and most worked in a cancer center or children's hospital (86%). Over half (63%) had been practicing for >15 years, and a majority saw patients ages 11 to 17. Although less than half reported discussing HPV vaccination with their patients, 69% were willing to become involved in HPV vaccine delivery. The most frequently reported barriers identified in our content analysis were related to system-level factors. Furthermore, providers identified opportunities within cancer prevention education, transitions in care, and at the system-level. Although barriers to HPV vaccination persist in cancer care, most providers perceived there to be opportunities to become involved in HPV vaccine delivery. Identifying strategies for PAYA oncology and hematology healthcare providers to adopt a stronger role in HPV vaccination remains a significant opportunity for future implementation research.
Prevention Relevance:
This mixed-methods study is the first to investigate and assess barriers and opportunities for HPV vaccine delivery among PAYA cancer healthcare providers. Our findings can serve as an important framework for future implementation research targeted towards HPV vaccine delivery in cancer clinical settings.

See related Spotlight, p. 545
Opportunities to Improve HPV Vaccination Among Pediatric, Adolescent, and Young Adult Cancer Survivors by Engaging both Oncology and Primary Care Teams
Authors: Butsch Kovacic Melinda , Topalian Alique , Erickson Melissa
Published: October 2023

The incidence of second primary cancers is rising particularly among pediatric, adolescent, and young adult (PAYA) cancer survivors. While human papillomavirus (HPV)-associated cancers can be prevented by vaccination, their uptake is lower and delayed in this group. Because a recommendation from a health care provider is the strongest predictor of HPV vaccination, there are great opportunities for PAYA cancer care providers to positively impact HPV vaccination rates. Prioritizing PAYA cancer care provider education as well as improving the education of and coordination with primary care providers are viewed as opportunities to encourage HPV vaccine uptake and prevent future cancers.

See related article by Garcia et al., p. 581
Spatio-Temporal Pattern Analysis of Forest Fire in Malang based on Remote Sensing using K-Means Clustering
Authors: Kirana Annisa Puspa , Astiningrum Mungki , Vista Candra Bella , Bhawiyuga Adhitya , Amrozi Aris Nur
Published: October 2023

Forest and land fire significantly impact the balance of the environment, such as haze pollution, destruction of ecosystems, the high release of carbon in the air, deterioration of health, and losses in various other fields. Based on these factors, developing an early warning system is essential to prevent forest fires, especially in forest and land areas. One of the data that can be used to monitor areas where there are frequent fires is hotspot data taken from the NASA MODIS Fire satellite. Data mining techniques are carried out to process the hotspot data so that the distribution of hotspot swarms is obtained. The data on the distribution of the clustering of hotspots are used to detect areas that are prone to fire from year to year. This study used the K-Means clustering algorithm. The data used in this study is hotspot data from Malang District, Indonesia. The range of hotspot data from January 2018 to June 2022. We use Silhouette coefficient testing to get the best number of classes in the cluster—this study's most recent application of the K-means clustering method to analyze hotspot distribution in a spatial-temporally. We use hotspot data in Malang's forest and land area using hotspot confidence levels >80%.
Social Media Exposure and Grammar Proficiency of Junior High School Students’: A Correlational Study
Authors: Otibar Jennen , Egargo Vanna , Calvara Caryl , Macion Karla , Abrugar Shiela Mae , Sanchez Alma Sonia Q. , Danday Billy A. , Calzita Catherine
Published: October 2023

Social media has emerged as a contemporary form of media with diverse attributes and characteristics. It serves as a means of instruction, and the younger generation frequently engages with it for various social interactions and communication purposes. While social media offers features not limited to education and is readily accessible to students, it can also impact certain academic aspects through this new digital medium. This study investigated the association between social media exposure and grammar proficiency among junior high school students, specifically spelling and punctuation marks usage. The researchers employed a correlational design and collected quantitative data. Through, total population sampling method, students from Grades 7, 8, 9, and 10 in a laboratory school in Eastern Visayas were chosen. The questionnaire included a spelling and punctuation examination, and the results were analyze using statistical methods such as mean, percentage, standard deviation, Pearson correlation (r), and Eta – correlation. This study's findings indicate no significant relationship between the grammar proficiency of the respondents and their social media exposure, as there is a relatively low correlation and association between the time spent on social media and grammar proficiency test scores. However, the study also revealed a positive correlation between age and grammar proficiency, implying that the older the respondents, the higher their knowledge about correct spelling and punctuation marks usage. Furthermore, the study also suggests conducting further research to explore the relationship between other components of grammar competency and specific social media platforms, such as TikTok, which has the highest hours of exposure.