bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 2 trial of a DNA vaccine (pTVG-HP) and nivolumab in patients with castration-sensitive non-metastatic (M0) prostate cancer
Authors: McNeel Douglas G , Emamekhoo Hamid , Eickhoff Jens C , Kyriakopoulos Christos E , Wargowski Ellen , Tonelli Tommaso P , Johnson Laura E , Liu Glenn
Published: December 2023

Purpose

We have previously reported that a plasmid DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) had greater clinical activity when given in combination with pembrolizumab to patients with metastatic, castration-resistant prostate cancer. The current trial was conducted to evaluate vaccination with PD-1 blockade, using nivolumab, in patients with early, recurrent (M0) prostate cancer.

Methods

Patients with M0 prostate cancer were treated with pTVG-HP (100 µg administered intradermally) and nivolumab (240 mg intravenous infusion) every 2 weeks for 3 months, and then every 4 weeks for 1 year of total treatment. Patients were then followed for an additional year off treatment. The primary objectives were safety and complete prostate-specific antigen (PSA) response (PSA<0.2 ng/mL).

Results

19 patients were enrolled. No patients met the primary endpoint of complete PSA response; however, 4/19 (21%) patients had a PSA decline >50%. Median PSA doubling times were 5.9 months pretreatment, 25.6 months on-treatment (p=0.001), and 9.0 months in the subsequent year off-treatment. The overall median radiographic progression-free survival was not reached. Grade 3 or 4 events included adrenal insufficiency, fatigue, lymphopenia, and increased amylase/lipase. 9/19 (47%) patients developed immune-related adverse effects (irAE). The development of irAE and increased CXCL9 were associated with increased PSA doubling time. Quantitative NaF PET/CT imaging showed the resolution of subclinical lesions along with the development of new lesions at each time point.

Conclusions

In this population, combining nivolumab with pTVG-HP vaccination was safe, and immunologically active, prolonged the time to disease progression, but did not eradicate disease. Quantitative imaging suggested that additional treatments targeting mechanisms of resistance may be required to eliminate tumors.

Trial registration number

NCT03600350.
Soil enzyme activities in heavily manured and waterlogged soil cultivated with ryegrass (Lolium multiflorum)
Authors: Rupngam Thidarat , Messiga Aimé J. , Karam Antoine
Published: December 2023

Extended waterlogging (WL) conditions can alter soil enzyme activities and their role in maintaining healthy soils. We assessed the effects of soil moisture regimes (field capacity [FC] and WL) and phosphorus (P) rates (0, 15, 30, 45 kg available P ha–1) on ( i) soil enzymes and microbial biomass carbon (MBC), microbial biomass nitrogen (MBN), and microbial biomass P (MBP); and ( ii) dissolved organic carbon (DOC) and total dissolved nitrogen (TDN). The treatments were tested in a 4-month greenhouse experiment using intact soil columns under annual ryegrass ( Lolium multiflorum). WL decreased the activity of β-glucosidase and acid phosphomonoesterase but increased N-acetyl-β-glucosaminidase in soils. These changes were associated with changes in MBC, DOC, MBN, and TDN, but not MBP. Anoxic conditions in WL soil promote the activity of anaerobes and contribute to the reduction of Fe oxyhydroxides and the release of DOC, TDN, and P in the soil solution. The activity of the extracellular enzymes decreased in WL with additions of slurry indicating adequate supply of C, N, and P. Our results also showed that both enzyme activities and microbial biomass were restricted in the upper soil layer with limited downward movement along the soil profile. We can conclude that since these enzymes control the hydrolysis of cellulose, phosphomonoester, and chitin, soil moisture influences the direction and magnitude of C, N, and P in manured and waterlogged soil cultivated with ryegrass.
Secret key rate bounds for quantum key distribution with faulty active phase randomization
Authors: Sixto Xoel , Currás-Lorenzo Guillermo , Tamaki Kiyoshi , Curty Marcos
Published: December 2023

Decoy-state quantum key distribution (QKD) is undoubtedly the most efficient solution to handle multi-photon signals emitted by laser sources, and provides the same secret key rate scaling as ideal single-photon sources. It requires, however, that the phase of each emitted pulse is uniformly random. This might be difficult to guarantee in practice, due to inevitable device imperfections and/or the use of an external phase modulator for phase randomization in an active setup, which limits the possible selected phases to a finite set. Here, we investigate the security of decoy-state QKD when the phase is actively randomized by faulty devices, and show that this technique is quite robust to deviations from the ideal uniformly random scenario. For this, we combine a novel parameter estimation technique based on semi-definite programming, with the use of basis mismatched events, to tightly estimate the parameters that determine the achievable secret key rate. In doing so, we demonstrate that our analysis can significantly outperform previous results that address more restricted scenarios.
Optimal Inapproximability with Universal Factor Graphs
Authors: Austrin Per , Brown-Cohen Jonah , Håstad Johan
Published: December 2023

The factor graph of an instance of a constraint satisfaction problem (CSP) is the bipartite graph indicating which variables appear in each constraint. An instance of the CSP is given by the factor graph together with a list of which predicate is applied for each constraint. We establish that many Max-CSPs remain as hard to approximate as in the general case even when the factor graph is fixed (depending only on the size of the instance) and known in advance.

Examples of results obtained for this restricted setting are:

(1)

Optimal inapproximability for Max-3-Lin and Max-3-Sat (Håstad, J. ACM 2001).

(2)

Approximation resistance for predicates supporting pairwise independent subgroups (Chan, J. ACM 2016).

(3)

Hardness of the “(2 + ϵ)-Sat” problem and other Promise CSPs (Austrin et al., SIAM J. Comput. 2017).

The main technical tool used to establish these results is a new way of folding the long code which we call “functional folding”.
Enhancing Low-Resource Sanskrit-Hindi Translation through Deep Learning with Ayurvedic Text
Authors: Sethi Nandini , Dev Amita , Bansal Poonam , Sharma Deepak Kumar , Gupta Deepak
Published: December 2023

The Machine Translation (MT) community is interested in Neural Machine Translation (NMT) because it can persevere continues data over a range of input and output phrase lengths. The NMT system employs a cutting-edge attention mechanism that enables concentrating on a particular input vector of the input sentence rather than obtaining an entire vector for every input sentence. While the Neural approach enhances translation superiority by addressing issues with enduring dependencies and making contextual analysis more accessible, it also requires a sufficient parallel corpus for training, which is challenging in dialects with limited resources. The primary goal of this research is to tackle the distinctive difficulties associated with translating Ayurvedic texts using neural machine translation (NMT). Ayurvedic texts pose unique challenges due to their specialized vocabulary and domain-specific terminology, necessitating a customized approach to achieve precise and meaningful translations. To create a reliable neural machine translation system for the Sanskrit-Hindi language pair, this study utilized a manually created parallel corpus containing Ayurvedic texts and general domain texts. With the help of this corpus, two NMT models were constructed: an attention-based transformer model (NMT2) and an attention-based encoder-decoder recurrent neural network (NMT1). These models integrated deep neural network techniques to optimize the translation process and overcome the constraints of limited training data and complex grammatical structures of Sanskrit. For Sanskrit-to-Hindi, the transformer-based approach received a higher average BLEU score of 48.1 percent and a uni-gram BLEU Score of 56.86 percent.
Extrachromosomal DNA: Biogenesis and Functions in Cancer
Authors: Curtis Ellis J. , Rose John C. , Mischel Paul S. , Chang Howard Y.
Published: December 2023

In cancer, oncogenes can untether themselves from chromosomes onto circular, extrachromosomal DNA (ecDNA) particles. ecDNA are common in many of the most aggressive forms of cancer of women and men and of adults and children, and they contribute to treatment resistance and shorter survival for patients. Hiding in plain sight and missing from cancer genome maps, ecDNA was not, until recently, widely recognized to be an important feature of cancer pathogenesis. However, extensive new data demonstrate that ecDNA is a frequent and potent driver of aggressive cancer growth and treatment failure that can arise early or late in the course of the disease. The non-Mendelian genetics of ecDNA lies at the heart of the problem. By untethering themselves from chromosomes, ecDNA are randomly distributed to daughter cells during cell division, promoting high oncogene copy number, intratumoral genetic heterogeneity, accelerated tumor evolution, and treatment resistance due to rapid genome change. Further, the circular shape of ecDNA, and its high level of chromatin accessibility, promotes oncogene transcription and generates unique enhancer–promoter interactions in cis, as well as cooperative regulatory interactions between ecDNA particles in trans. In this review, we discuss the state of the field and its implications for patients with oncogene-amplified cancers.
Obsessive–Compulsive Disorder in Children and Adolescents
Authors: Stiede Jordan T. , Spencer Samuel D. , Onyeka Ogechi , Mangen Katie H. , Church Molly J. , Goodman Wayne K. , Storch Eric A.
Published: December 2023

Obsessive–compulsive disorder (OCD) in children and adolescents is a neurobehavioral condition that can lead to functional impairment in multiple domains and decreased quality of life. We review the clinical presentation, diagnostic considerations, and common comorbidities of pediatric OCD. An overview of the biological and psychological models of OCD is provided along with a discussion of developmental considerations in youth. We also describe evidence-based treatments for OCD in childhood and adolescence, including cognitive behavioral therapy (CBT) with exposure and response prevention (ERP) and pharmacotherapy. Finally, research evaluating the delivery of CBT in different formats and modalities is discussed, and we conclude with suggestions for future research directions.
The Economics of Treatment for Depression
Authors: Stecher Chad , Cloonan Sara , Domino Marisa Elena
Published: December 2023

The global prevalence of depression has risen over the past three decades across all socioeconomic groups and geographic regions, with a particularly rapid increase in prevalence among adolescents (aged 12–17 years) in the United States. Depression imposes large health, economic, and societal costs, including reduced life span and quality of life, medical costs, and reduced educational attainment and workplace productivity. A wide range of treatment modalities for depression are available, but socioeconomic disparities in treatment access are driven by treatment costs, lack of culturally tailored options, stigma, and provider shortages, among other barriers. This review highlights the need for comparative research to better understand treatments’ relative efficacy, cost-effectiveness, scalability, and potential heterogeneity in efficacy across socioeconomic groups and country and cultural contexts. To address the growing burden of depression, mental health policy could consider reducing restrictions on the supply of providers, implementing digital interventions, reducing stigma, and promoting healthy lifestyles.
Electrolytic Reduction of CO2 Using Perovskite-Type La-Based Oxide Anodes in Chloride Molten Salts
Authors: Kimura S. , Tanaka S. , Suzuki Y. , Murata S. , Fukumoto T. , Goto T.
Published: December 2023

CO2 decomposition in molten salt is an attractive process as a new method for achieving carbon neutrality, for which the development of inert anodes and electrolytic bath suitable for CO2 decomposition is essential. Previous studies mostly investigated the electrode material but did not investigate the relationship between the electrolysis bath and electrode reaction. The effects of the electrolytic bath on anode reaction and the development of inert anode material with high current density were investigated in this study. Electrolytic bath of LiCl–CaCl2 and NaCl–CaCl2 with similar oxide solubilities were compared, finding that LiCl–CaCl2 melts exhibited higher oxidation current density in cyclic voltammetry and more stable potential transition in galvanostatic electrolysis. Among the five anodes with a perovskite-type La-based oxide were investigated, La0.6Sr0.4CoO3−δ
showed the highest electrical conductivity and the largest increase in oxidation current density. CO2 decomposition tests were performed in LiCl–CaCl2 with CaO and CaCO3 added as a CO2 source at 873 K using La0.6Sr0.4CoO3−δ
anode. Only C and O2 were recovered from CO2 by electrolysis test. The current efficiencies were 78.3% and 54.4%, respectively. The La0.6Sr0.4CoO3−δ
anode exhibited excellent corrosion resistance, demonstrating its potential as a promising inert anode for CO2 decomposition.
Silicon-Based Anode and Its Full-Cell Performance Test Using a High-Capacity Pouch Cell
Authors: Thapa Arun , Gao Hongwei
Published: December 2023

Despite impressive theoretical capacity, silicon (Si) electrodes suffer from severe pulverization due to enormous volume change. The pulverization leads to low electrical conductivity and reduced diffusivity of lithium ions, resulting in poor rate and cycling ability. In this work, the electrical conductivity of Si electrodes is improved by incorporating carbon nanotubes (CNTs) to enhance the rate and cycling ability. The incorporation of CNTs in the Si electrode is optimized systematically based on the electrode conductivity and cycling performance. Furthermore, the importance of nano-sized conductive carbon in the electrode for achieving an integrated conductive hybrid network across the entire bulk electrode that meets short-range and long-range conduction requirements for the enhancement of electrochemical reactions is explained. The SiCNTs (SiCNTs-30) assessed using coin-type half cells exhibited a higher specific capacity of ∼980 mAh g−1 after 100 cycles at the current density of 0.25 A g−1. Also, the cyclability tests of the SiCNTs-30 anode, paired with the commercial cathode, at the pouch cell level revealed an impressive specific capacity of more than 556 mAh g−1 at 1 C after 500 cycles. Hence, the method shown in this work can pave the way for commercializing SiCNTs hybrid anodes for high-energy and high-power lithium-ion batteries.
Method—Time-Variance In EIS Measurements: The Simple Case of Dilution
Authors: Murer Nicolas , Diard Jean-Paul , Petrescu Bogdan
Published: December 2023

Classical analysis of Electrochemical Impedance Spectroscopy (EIS) measurements requires them to be performed on a linear, time-invariant system. Many electrochemical systems are time-variant (battery under charge/discharge, corroding sample). The effect of time-variance on these systems is not easy to study because there is no reference to which the time-variant results could be compared to. In this paper, we perform a simple dilution experiment to illustrate the time-variance on EIS measurements performed in a quiescent solution and at a Rotating Disk Electrode (RDE), in an electrolyte containing the classical K3Fe(CN)6/K4Fe(CN)6 redox couple. Using simulations based on analytical expressions of the Faradaic impedance, experimental parameters are defined. Fitting EIS data using Equivalent Circuit Models (ECM allows us to qualify the errors made when trying to fit time-variant data with time-invariant impedance expressions. Repeated impedance measurements and reconstruction of instantaneous impedance graphs via interpolation allows to reduce the effect of time-variance and improve the fitting quality. Finally, another approach is presented, which consists in fitting the time-variant data by an analytical time-dependent expression of the Faradaic impedance where the concentration evolution and its effect are accounted for.
Effect of Dry Etching to Improve Ohmic Contacts on Bulk, Lightly-Doped β-Ga2O3
Authors: Chiang Chao-Ching , Li Jian-Sian , Wan Hsiao-Hsuan , Ren Fan , Pearton Stephen J.
Published: December 2023

Ti/Au is a typical Ohmic metal contact stack to n-type β-Ga2O3 but there have been few systematic studies of the use of pre-exposure of the surface to plasmas prior to metal deposition in order to lower the contact resistance. The effects of Cl2/Ar Inductively Coupled Plasma exposure of Ga2O3 surfaces prior to deposition of Ti/Au (20/80 nm) contacts were examined through circular transfer length method (CTLM) measurements to determine both the contact resistance and specific contact resistivity. ICP source power, which controls ion density in the plasma is found to be more important than ion energy (∼165–490 eV in these experiments). The plasma exposure improved specific contact resistivity by more than a factor of 2 in all cases for lightly n-type (1017 cm−3) Ga2O3 and a minimum value of 2 × 10−4 Ω.cm2 was obtained after heating at 550 °C.
Design Considerations into Circuit Applications for Structurally Optimised FinFET
Authors: Sarangam K. , Valasa Sresta , Mudidhe Praveen Kumar , Narendar Vadthiya , Kotha Venkata Ramakrishna , Bhukya Sunitha , Bheemudu V. , Pothalaiah S.
Published: December 2023

FinFETs have gained a lot of demand in the family of multigate FET devices in the recent years. In this view, this manuscript aims to design different FinFET architectures to observe the analog and circuit performance. A total of five structures namely Conventional FinFET, Lightly doped S/D, Underlap FinFET, Single-k spacer, and Dual-k spacer FinFET has been designed and performance has been analysed. The best performance is obtained for dual-k spacer FinFET. Moreover, the dimensional variations such as gate length (Lg), fin width (Wfin) and fin height (Hfin) for the duak-k spacer FinFET is performed and it is found that lowering the Lg and Wfin, and increasing the Hfin would be a better option in order to enhance the device performance. Furthermore, at the optimized device dimensions the circuit analysis for inverter and single stage common source amplifier is performed. The gain for the designed single stage common stage amplifier is noticed to be 1.8155.
Effects of Vitamin E on Immune Response, Antioxidant Capacity, and Liver Tissue Structure of Crucian Carp under Acute Cold Stress
Authors: Tang Jiaming , Zhang Changfeng , Jiang Lexia , Chen Dongjie , Jiang Peihong , Huang Baosheng
Published: December 2023

The purpose of this study was to investigate the effects of vitamin E addition to the water column on immune response, antioxidant capacity, and liver tissue structure of crucian carp (Carassius auratus) under acute cold stress. Crucian carp was placed in the aqueous solution of control group (E1), negative control group (E2), and 100 mg/L vitamin E (E3) and cooled from 20 to 5°C by cold acclimation intelligent cooling device. Samples were taken at three temperature points of 20, 10, and 5°C, respectively, and the samples were detected and analyzed. The results showed that the content of each index increased under acute cold stress. The contents of white blood cell, red blood cell, hemoglobin, platelet, lysozyme, and glutathione peroxidase in E3 treatment group were significantly lower than those in E1 and E2 treatment groups (

P
<
0.05

). The contents of cholinesterase, alkaline phosphatase, acid phosphatase, hydrogen peroxide, superoxide anion, superoxide dismutase, peroxidase, and malondialdehyde in E3 treatment group were significantly lower than those in E1 and E2 treatment groups (

P
<
0.01

). Under acute cold stress, the liver tissue structure of crucian carp also changed, such as hepatocyte vacuolization, and the damage degree of E3 treatment group was lower than that of E1 and E2 treatment groups. In summary, the addition of vitamin E in water to treat crucian carp can reduce the harm caused by acute cold stress to its body and provide a theoretical reference for the application of vitamin E in water to alleviate fish stress.
The Fuzzy Prime Spectrum of Partially Ordered Sets
Authors: Engidaw Derso Abeje , Addis Gezahagne Mulat , Norahun Wondwosen Zemene , Boku Dereje Kifle , Demrew Habtu Bayafers , Degefa Tewodros Argachew
Published: December 2023

We study the space of prime fuzzy ideals (and the space of maximal fuzzy ideals as a subspace) equipped with the hull‐kernel topology in partially ordered sets. Mainly, we investigate the conditions for which the fuzzy prime spectrum of a poset is compact, Hausdorff, and normal, respectively.
Numerical Solution of Fractional Order Integro-Differential Equations via Müntz Orthogonal Functions
Authors: Akhlaghi S. , Tavassoli Kajani M. , Allame M.
Published: December 2023

In this paper, we derive a spectral collocation method for solving fractional-order integro-differential equations by using a kind of Müntz orthogonal functions that are defined on

0,1

and have simple and real roots in this interval. To this end, we first construct the operator of Riemann–Liouville fractional integral corresponding to this kind of Müntz functions. Then, using the Gauss–Legendre quadrature rule and by employing the roots of Müntz functions as the collocation points, we arrive at a system of algebraic equations. By solving this system, an approximate solution for the fractional-order integro-differential equation is obtained. We also construct an upper bound for the truncation error of Müntz orthogonal functions, and we analyze the error of the proposed collocation method. Numerical examples are included to demonstrate the validity and accuracy of the method.
Evolutionary Game Model of Civil Aviation and High-Speed Rail Interaction Strategies Based on the Passenger Ticket and Carbon Trading Prices
Authors: Sun Bo , Xu Zehui , Wei Ming
Published: December 2023

This study elaborated an evolutionary game model to optimize the decision-making process on the interaction between civil aviation and high-speed rail under alternative passenger ticket prices (PTPs) and carbon trading prices (CTPs). First, a logit model was used to calculate the passenger flow distribution rate in civil aviation and HSR, and their revenue loss function was determined according to varying PTPs and CTPs. Second, an evolutionary game model with incomplete information was developed to assess the respective revenues. Third, the stable strategy solution of the game model was derived from replicator dynamics, and an investigation of stable conditions under variable cases was performed. Finally, the simulation of a case study on the Beijing–Shanghai corridor was conducted to validate the proposed model’s feasibility. The additional revenue is shown to be the key influencing factor, mainly controlling the strategic decisions of airport and high-speed rail companies. Besides, the final strategy was strongly influenced by the alteration of PTPs and CTPs: higher PTPs promoted civil aviation and high-speed rail collaboration, while increased CTPs forced their competing behavior. The results obtained are instrumental in outlining the optimal strategy range for passenger ticket and carbon trading prices, encouraging high-speed transportation system growth.
Semi‐White‐Box Strategy: Enhancing Data Efficiency and Interpretability of Convolutional Neural Networks in Image Processing
Authors: Wang Qi , Zeng Jianchao , Qin Pinle , Zhao Pengcheng , Chai Rui , Yang Zhaomin , Zhang Jianshan
Published: December 2023

Data‐hunger is a persistent challenge in machine learning, particularly in the field of image processing based on convolutional neural networks (CNNs). This study systematically investigates the factors contributing to data‐hunger in machine‐learning‐based image‐processing algorithms. The results revealed that the proliferation of model parameters, the lack of interpretability, and the complexity of model structure are significant factors influencing data‐hunger. Based on these findings, this paper introduces a novel semi‐white‐box neural network model construction strategy. This approach effectively reduces the number of model parameters while enhancing the interpretability of model components. It accomplishes this by constraining uninterpretable processes within the model and leveraging prior knowledge of image processing for model. Rather than relying on a single all‐in‐one model, a semi‐white‐box model is composed of multiple smaller models, each responsible for extracting fundamental semantic features. The final output is derived from these features and prior knowledge. The proposed strategy holds the potential to substantially decrease data requirements under specific data source conditions while improving the interpretability of model components. Validation experiments are conducted on well‐established datasets, including MNIST, Fashion MNIST, CIFAR, and generated data. The results demonstrate the superiority of the semi‐white‐box strategy over the traditional all‐in‐one approach in terms of accuracy when trained with equivalent data volumes. Impressively, on the tested datasets, a simplified semi‐white‐box model achieves performance close to that of ResNet while utilizing a small number of parameters. Furthermore, the semi‐white‐box strategy offers improved interpretability and parameter reusability features that are challenging to achieve with the all‐in‐one approach. In conclusion, this paper contributes to mitigating data‐hunger challenges in machine‐learning‐based image processing through the introduction of a novel semi‐white‐box model construction strategy, backed by empirical evidence of its effectiveness.
Data from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Mukhopadhyay Suman , Huang Hsin-Yi , Lin Ziyan , Ranieri Michela , Li Shuai , Sahu Soumyadip , Liu Yingzhuo , Ban Yi , Guidry Kayla , Hu Hai , Lopez Alfonso , Sherman Fiona , Tan Yi Jer , Lee Yeuan Ting , Armstrong Amanda P. , Dolgalev Igor , Sahu Priyanka , Zhang Tinghu , Lu Wenchao , Gray Nathanael S. , Christensen James G. , Tang Tracy T. , Velcheti Vamsidhar , Khodadadi-Jamayran Alireza , Wong Kwok-Kin , Neel Benjamin G.
Published: December 2023

Abstract
Non–small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine–threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic.
Significance:
Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies.

See related commentary by Johnson and Haigis, p. 4005
Differences in Survival between Black and White Patients with Head and Neck Squamous Cell Carcinoma: Comparison of Data from the DOD Central Cancer Registry and SEER
Authors: Lin Jie , Orestes Michael I. , Shriver Craig D. , Zhu Kangmin
Published: December 2023

Background:

Barriers to health care access may contribute to the poorer survival of Black patients with head and neck squamous cell carcinoma (HNSCC) than their White counterparts in the U.S. general population. The Department of Defense's (DOD) Military Health System (MHS) provides universal health care access to all beneficiaries with various racial backgrounds.

Methods:

We compared overall survival of patients with HNSCC by race in the MHS and the general population, respectively, to assess whether there were differences in racial disparity between the two populations. The MHS patients were identified from the DOD's Central Cancer Registry (CCR) and the patients from the U.S. general population were identified from the NCI's Surveillance, Epidemiology and End Results (SEER) program. For each cohort, a retrospective study was conducted comparing survival by race.

Results:

Black and White patients in the CCR cohort had similar survival in multivariable Cox regression models with a HR of 1.04 and 95% confidence interval (95% CI) of 0.81 to 1.33 after adjustment for the potential confounders. In contrast, Black patients in the SEER cohort exhibited significantly worse survival than White patients with an adjusted HR of 1.47 (95% CI = 1.43–1.51). These results remained similar in the subgroup analyses for oropharyngeal and non-oropharyngeal sites, respectively.

Conclusions:

There was no racial difference in survival among patients with HNSCC in the MHS system, while Black patients had significantly poorer survival than White patients in the general population.

Impact:

Equal access to health care could reduce racial disparity in overall survival among patients with HNSCC.
Supplementary Figure 1 from Phase I Trial of the Multi-kinase Inhibitor Cabozantinib, a CYP3A4 Substrate, plus CYP3A4-Interacting Antiretroviral Therapy in People Living with HIV and Cancer (AMC-087)
Authors: Haigentz Missak , Lee Jeannette Y. , Chiao Elizabeth Y. , Aboulafia David M. , Ratner Lee , Ambinder Richard F. , Baiocchi Robert A. , Mitsuyasu Ronald T. , Wachsman William , Sparano Joseph A. , Rudek Michelle A.
Published: December 2023

Supplementary Figure 1. Average and standard deviation concentration–time profile of cabozantinib at steady-state on a semi-log plot for stratum A (A), stratum B (B), and stratum C (C). Doses are noted in the figures.
Supplementary Table S4 from SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials
Authors: Conte Benedetta , Boni Luca , Bisagni Giancarlo , Durando Antonio , Sanna Giovanni , Gori Stefania , Garrone Ornella , Tamberi Stefano , De Placido Sabino , Schettini Francesco , Pazzola Antonio , Ponzone Riccardo , Montemurro Filippo , Lunardi Gianluigi , Notaro Rosario , De Angioletti Maria , Turletti Anna , Mansutti Mauro , Puglisi Fabio , Frassoldati Antonio , Porpiglia Mauro , Fabi Alessandra , Generali Daniele , Scognamiglio Giovanni , Rossi Maura , Brasó-Maristany Fara , Prat Aleix , Cardinali Barbara , Piccioli Patrizia , Serra Martina , Lastraioli Sonia , Bighin Claudia , Poggio Francesca , Lambertini Matteo , Del Mastro Lucia
Published: December 2023

Patients’ characteristics SNP rs4646
Supplementary Figure S5 from Phase II Trial of Nivolumab in Metastatic Rare Cancer with dMMR or MSI-H and Relation with Immune Phenotypic Analysis (the ROCK Trial)
Authors: Okuma Hitomi S. , Watanabe Keisuke , Tsuchihashi Kenji , Machida Ryunosuke , Sadachi Ryo , Hirakawa Akihiro , Ariyama Hiroshi , Kanai Masashi , Kamikura Masahisa , Anjo Kenta , Hiramitsu Akari , Sekine Shigeki , Okita Natsuko , Mano Hiroyuki , Nishikawa Hiroyoshi , Nakamura Kenichi , Yonemori Kan
Published: December 2023

Supplementary Figure S5: T-BET and PD-1 expression on the CD8+ T cells at the base line (related with the main figure 3).
Supplementary Figure S3 from Phase II Trial of Nivolumab in Metastatic Rare Cancer with dMMR or MSI-H and Relation with Immune Phenotypic Analysis (the ROCK Trial)
Authors: Okuma Hitomi S. , Watanabe Keisuke , Tsuchihashi Kenji , Machida Ryunosuke , Sadachi Ryo , Hirakawa Akihiro , Ariyama Hiroshi , Kanai Masashi , Kamikura Masahisa , Anjo Kenta , Hiramitsu Akari , Sekine Shigeki , Okita Natsuko , Mano Hiroyuki , Nishikawa Hiroyoshi , Nakamura Kenichi , Yonemori Kan
Published: December 2023

Supplementary Figure S3: Gating strategy for immune phenotyping analysis.
Supplementary Table S4 from Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma
Authors: Marino-Enriquez Adrian , Novotny Jan Philipp , Gulhan Doga C. , Klooster Isabella , Tran Antuan V. , Kasbo Macy , Lundberg Meijun Z. , Ou Wen-Bin , Tao Derrick L. , Pilco-Janeta Daniel F. , Mao Victor Y. , Zenke Frank T. , Leeper Brittaney A. , Gokhale Prafulla C. , Cowley Glenn S. , Baker Laurence H. , Ballman Karla V. , Root David E. , Albers Joachim , Park Peter J. , George Suzanne , Fletcher Jonathan A.
Published: December 2023

Supplementary Table S4:
Molecular features of patient-derived LMS models used in these studies (three LMS cells lines and one LMS PDX), including clinical features of LMS tumors from Dana-Farber/Brigham and Women’s Hospital from which they were derived
Supplementary Table S3 from Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma
Authors: Marino-Enriquez Adrian , Novotny Jan Philipp , Gulhan Doga C. , Klooster Isabella , Tran Antuan V. , Kasbo Macy , Lundberg Meijun Z. , Ou Wen-Bin , Tao Derrick L. , Pilco-Janeta Daniel F. , Mao Victor Y. , Zenke Frank T. , Leeper Brittaney A. , Gokhale Prafulla C. , Cowley Glenn S. , Baker Laurence H. , Ballman Karla V. , Root David E. , Albers Joachim , Park Peter J. , George Suzanne , Fletcher Jonathan A.
Published: December 2023

Supplementary Table S3:
List of pathogenic or likely pathogenic mutations in LMS based on 1) ClinVar (20); 2) functional classification as deleterious by both SIFT (21) and PolyPhen (22); and 3) truncating nature of the mutation.
Supplementary Table S2 from Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma
Authors: Marino-Enriquez Adrian , Novotny Jan Philipp , Gulhan Doga C. , Klooster Isabella , Tran Antuan V. , Kasbo Macy , Lundberg Meijun Z. , Ou Wen-Bin , Tao Derrick L. , Pilco-Janeta Daniel F. , Mao Victor Y. , Zenke Frank T. , Leeper Brittaney A. , Gokhale Prafulla C. , Cowley Glenn S. , Baker Laurence H. , Ballman Karla V. , Root David E. , Albers Joachim , Park Peter J. , George Suzanne , Fletcher Jonathan A.
Published: December 2023

Supplementary Table S2:
Sig3 scores and FGA values in LMS tumor samples. Sig3+ samples are predicted with a classifier trained in WGS LMS data. FGA values are calculated on CNVkit-based copy number profiles (see methods).
Supplementary Figure S9 from Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma
Authors: Marino-Enriquez Adrian , Novotny Jan Philipp , Gulhan Doga C. , Klooster Isabella , Tran Antuan V. , Kasbo Macy , Lundberg Meijun Z. , Ou Wen-Bin , Tao Derrick L. , Pilco-Janeta Daniel F. , Mao Victor Y. , Zenke Frank T. , Leeper Brittaney A. , Gokhale Prafulla C. , Cowley Glenn S. , Baker Laurence H. , Ballman Karla V. , Root David E. , Albers Joachim , Park Peter J. , George Suzanne , Fletcher Jonathan A.
Published: December 2023

Supplementary Figure S9:
Cell proliferation assay (BrdU incorporation) demonstrates that combination of DNA-PK inhibition with
low-dose doxorubicin reduces LMS03 and LMS05 cell proliferation compared to either drug alone.
Peposertib and AZD7648 are structurally unrelated DNA-PK inhibitors. Cells were treated for 7 days
with each drug and the combinations at the indicated doses; BrdU incorporation over 24h was
measured at day 7 with a luminescence-based ELISA assay (Roche)
Supplementary Table S4 from CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer
Authors: Huang Huanhuan , Yao Yao , Shen Lesang , Jiang Jingxin , Zhang Ting , Xiong Jia , Li Jiaxin , Sun Shanshan , Zheng Siwei , Jia Fang , Zhou Jun , Yu Xiuyan , Chen Wuzhen , Shen Jun , Xia Wenjie , Shao Xuan , Wang Qingqing , Huang Jian , Ni Chao
Published: December 2023

Table. S4. Characteristics of the patient samples and basic information.
Figure S9 from Lenvatinib, Toripalimab plus FOLFOX Chemotherapy in Hepatocellular Carcinoma Patients with Extrahepatic Metastasis: A Biomolecular Exploratory, Phase II Trial (LTSC)
Authors: He MinKe , Huang YeXing , Du ZeFeng , Lai ZhiCheng , Ouyang Hanyue , Shen JingXian , Wen DongSheng , Li QiJiong , Zhang YaoJun , Wei Wei , Chen MinShan , Xu Li , Kan Anna , Shi Ming
Published: December 2023

Representative images of patient eight.
Figure S6 from Lenvatinib, Toripalimab plus FOLFOX Chemotherapy in Hepatocellular Carcinoma Patients with Extrahepatic Metastasis: A Biomolecular Exploratory, Phase II Trial (LTSC)
Authors: He MinKe , Huang YeXing , Du ZeFeng , Lai ZhiCheng , Ouyang Hanyue , Shen JingXian , Wen DongSheng , Li QiJiong , Zhang YaoJun , Wei Wei , Chen MinShan , Xu Li , Kan Anna , Shi Ming
Published: December 2023

Representative images of patient five.
Data from Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer
Authors: Shagisultanova Elena , Gradishar William , Brown-Glaberman Ursa , Chalasani Pavani , Brenner Andrew J. , Stopeck Alison , Parris Hannah , Gao Dexiang , McSpadden Tessa , Mayordomo Jose , Diamond Jennifer R. , Kabos Peter , Borges Virginia F.
Published: December 2023

AbstractPurpose:
To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC).
Patients and Methods:
Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS).
Results:
Forty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10–19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year.
Conclusions:
TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing.

See related commentary by Huppert and Rugo, p. 4993
Data from The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 After Progression on Rucaparib
Authors: Brown Timothy J. , Yablonovitch Arielle , Till Jacob E. , Yen Jennifer , Kiedrowski Lesli A. , Hood Ryan , O'Hara Mark H. , Teitelbaum Ursina , Karasic Thomas B. , Schneider Charles , Carpenter Erica L. , Nathanson Katherine , Domchek Susan M. , Reiss Kim A.
Published: December 2023

Abstract
Purpose: Poly-(ADP-ribose) polymerase inhibitors provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. Experimental Design: We collected paired cfDNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease. Results: Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (mPFS 3.7mo vs 12.5mo, p=0.001) and poor overall survival (mOS 6.2mo vs 23.0mo, p<0.0001). All patients with reversions received re-challenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (rwTTD 2.4mo vs 5.8mo, p = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second line therapy was significantly lower in those with reversion variants than in those without (5.5mo vs 12.0 mo, p = 0.002). Finally, high levels tumor shedding were independently associated with poor outcomes in patients who received rucaparib. Conclusions: Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA or PALB2 related PDAC who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment and poor overall survival of patients. The identification of such variants in the blood may have both predictive and prognostic value.
Data from The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib
Authors: Brown Timothy J. , Yablonovitch Arielle , Till Jacob E. , Yen Jennifer , Kiedrowski Lesli A. , Hood Ryan , O'Hara Mark H. , Teitelbaum Ursina , Karasic Thomas B. , Schneider Charles , Carpenter Erica L. , Nathanson Katherine , Domchek Susan M. , Reiss Kim A.
Published: December 2023

AbstractPurpose:
PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized.
Experimental Design:
We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease.
Results:
Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib.
Conclusions:
Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value.

See related commentary by Tsang and Gallinger, p. 5005
Data from Cancer-associated fibroblast-like tumor cells remodel the Ewing sarcoma tumor microenvironment
Authors: Wrenn Emma D. , Apfelbaum April A. , Rudzinski Erin R. , Deng Xuemei , Jiang Wei , Sud Sudha , Van Noord Raelene A. , Newman Erika A. , Garcia Nicolas M. , Miyaki Aya , Hoglund Virginia J. , Bhise Shruti S. , Kanaan Sami B. , Waltner Olivia G. , Furlan Scott N. , Lawlor Elizabeth R.
Published: December 2023

Abstract
Purpose: Despite limited genetic and histologic heterogeneity, Ewing sarcoma (EwS) tumor cells are transcriptionally heterogeneous and display varying degrees of mesenchymal lineage specification in vitro. In this study, we investigated if and how transcriptional heterogeneity of EwS cells contributes to heterogeneity of tumor phenotypes in vivo. Experimental Design: Single cell proteogenomic-sequencing of EwS cell lines was performed and integrated with patient tumor transcriptomic data. Cell subpopulations were isolated by FACS for assessment of gene expression and phenotype. Digital spatial profiling and human whole transcriptome analysis interrogated transcriptomic heterogeneity in EwS xenografts. Tumor cell subpopulations and matrix protein deposition were evaluated in xenografts and patient tumors using multiplex immunofluorescence staining. Results: We identified CD73 as a biomarker of highly mesenchymal EwS cell subpopulations in tumor models and patient biopsies. CD73+ tumor cells displayed distinct transcriptional and phenotypic properties, including selective upregulation of genes that are repressed by EWS::FLI1, and increased migratory potential. CD73+ cells were distinguished in vitro and in vivo by increased expression of matrisomal genes and abundant deposition of extracellular matrix (ECM) proteins. In epithelial-derived malignancies, ECM is largely deposited by cancer-associated fibroblasts (CAFs) and we thus labeled CD73+ EwS cells, CAF-like tumor cells. Marked heterogeneity of CD73+ EwS cell frequency and distribution were detected in tumors in situ, and CAF-like tumor cells and associated ECM were observed in peri-necrotic regions and invasive foci. Conclusions: EwS tumor cells can adopt CAF-like properties and these distinct cell subpopulations contribute to tumor heterogeneity by remodeling the tumor microenvironment.
Supplementary Vignette 2 from Building Tools for Machine Learning and Artificial Intelligence in Cancer Research: Best Practices and a Case Study with the PathML Toolkit for Computational Pathology
Authors: Rosenthal Jacob , Carelli Ryan , Omar Mohamed , Brundage David , Halbert Ella , Nyman Jackson , Hari Surya N. , Van Allen Eliezer M. , Marchionni Luigi , Umeton Renato , Loda Massimo
Published: December 2023

In this vignette, we demonstrate a practical example of a complete PathML workflow for analyzing brightfield H&E images.
Supplementary Figure 1 from Building Tools for Machine Learning and Artificial Intelligence in Cancer Research: Best Practices and a Case Study with the PathML Toolkit for Computational Pathology
Authors: Rosenthal Jacob , Carelli Ryan , Omar Mohamed , Brundage David , Halbert Ella , Nyman Jackson , Hari Surya N. , Van Allen Eliezer M. , Marchionni Luigi , Umeton Renato , Loda Massimo
Published: December 2023

Supplementary Figure 1 shows some examples of the transformations which form the building blocks of preprocessing pipelines.
TABLE 2 from Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer
Authors: Malhi Vikram , Agarwal Priya , Gates Mary R. , Liu Lichuan , Wang Jianshuang , De Bruyn Tom , Lam Scott , Eng-Wong Jennifer , Perez-Moreno Pablo , Chen Ya-Chi , Yu Jiajie
Published: December 2023

Giredestrant steady-state pharmacokinetic parameters (escalation cohorts)