bluuebunny/crossref_metadata_2025 huggingface dataset:
Best evidence topic report: are portable handheld fundus cameras effective in diagnosing diabetic retinopathy in emergency settings?
Authors: Arzaghi Mohammadreza , Alavi-Moghaddam Mostafa
Published: August 2024

A short-cut systematic review was conducted using a described protocol. The three-part question addressed was: In adult patients presenting to the ED with diabetes-related visual symptoms, how effective is using a portable handheld fundus camera in diagnosing diabetic retinopathy?

MEDLINE, Embase and Cochrane databases were searched for relevant evidence. Altogether, 237 papers were found using the search strategy developed. 12 provided the best evidence to answer the three-part question. The data on first author name, publication year, country of origin, study type, study sample size, participant’s gender, reported effect sizes, main findings and limitations were extracted from the relevant studies and listed in a table.

Following a thorough examination and review of the literature, our analysis identified 12 articles for detailed evaluation. Of these, three provided the most compelling evidence concerning the use of portable handheld fundus cameras for the diagnosis of diabetic retinopathy in emergency settings. Ruanet al(2022) reported superior image quality and a sensitivity of 82.1% (95% CI: 72.1% to 92.2%) with a specificity of 97.4% (95% CI: 95.4% to 99.5%) for a handheld camera combined with artificial intelligence interpretation. Jinet al(2017) demonstrated high-quality images with 63% rated as excellent, showing a comparable efficacy to a traditional tabletop camera. Daset al(2022) found that Remidio and Pictor handheld cameras had high success rates and image quality, with sensitivities of 77.5% (95% CI: 65.9% to 89.0%) and 78.1% (95% CI: 66.6% to 89.5%), respectively, comparable to the Zeiss tabletop camera’s sensitivity of 84.9% (95% CI: 78.2% to 91.5%). The clinical bottom line is that the best available evidence supports the effectiveness of portable handheld fundus cameras for diagnosing diabetic retinopathy in emergency settings.
One side effect: two networks? Lateral and posteromedial stimulation spreads induce dysarthria in subthalamic deep brain stimulation for Parkinson’s disease
Authors: Jergas Hannah , Petry-Schmelzer Jan Niklas , Hannemann Jonathan H , Thies Tabea , Strelow Joshua N , Rubi-Fessen Ilona , Quinting Jana , Baldermann Juan Carlos , Mücke Doris , Fink Gereon R , Visser-Vandewalle Veerle , Dembek Till A , Barbe Michael T
Published: August 2024

Background

Stimulation-induced dysarthria (SID) is a troublesome and potentially therapy-limiting side effect of deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson’s disease (PD). To date, the origin of SID, and especially whether there is an involvement of cerebellar pathways as well as the pyramidal tract, remains a matter of debate. Therefore, this study aims to shed light on structural networks associated with SID and to derive a data-driven model to predict SID in patients with PD and STN-DBS.

Methods

Randomised, double-blinded monopolar reviews determining SID thresholds were conducted in 25 patients with PD and STN-DBS. A fibre-based mapping approach, implementing the calculation of fibr-wise ORs for SID, was employed to identify the distributional pattern of SID in the STN’s vicinity. The ability of the data-driven model to classify stimulation volumes as ‘causing SID’ or ‘not causing SID’ was validated by calculating receiver operating characteristics (ROC) in an independent out-of-sample cohort comprising 14 patients with PD and STN-DBS.

Results

Local fibre-based stimulation maps showed an involvement of fibres running lateral and posteromedial to the STN in the pathogenesis of SID, independent of the investigated hemisphere. ROC analysis in the independent out-of-sample cohort resulted in a good fit of the data-driven model for both hemispheres (area under the curve (AUC)left=0.88, AUCright=0.88).

Conclusions

This study reveals an involvement of both, cerebello-thalamic fibres, as well as the pyramidal tract, in the pathogenesis of SID in STN-DBS. The results may impact future postoperative programming strategies to avoid SID in patients with PD and STN-DBS

Trial registration number

DRKS00023221; German Clinical Trials Register (DRKS) Number.
The Vulnerability-Adaptive Protection Paradigm
Authors: Wan Zishen , Gan Yiming , Yu Bo , Liu Shaoshan , Raychowdhury Arijit , Zhu Yuhao
Published: August 2024

Dek:

Moving toward reliable autonomous machines.
The Functional, the Imperative, and the Sudoku: Getting Good, Bad, and Ugly to Get Along (Functional Pearl)
Authors: Serrano Manuel , Findler Robert Bruce
Published: August 2024

Conventional wisdom suggests that the benefits of functional programming no longer apply in the presence of even a small amount of imperative code, as if the addition of imperative code effectively subtracts. And yet, as we show in this paper, combining functional programming with the special imperative language Esterel provides a multiplicative improvement to the benefits of functional programming.

The key to the benefit of both Esterel and functional programming stems from a restriction that both share. As in functional programming, where only the inputs to a function determine its outputs, the state of an Esterel computation is fully determined by the program’s input and the state that the computation had in the previous time step, where the notion of a time step is explicit in the language. Esterel’s guarantee holds even though Esterel programs feature concurrent threads, mutable state, and the ability to create, suspend, and even terminate threads as the computation proceeds. This similarity is the root of the benefits that programmers accrue as they informally reason about their program’s behavior.

To illustrate these benefits, the bulk of this paper consists of an in-depth exploration of HipHop code (a mashup of JavaScript and Esterel) that implements a Sudoku solver, showing how it is possible to write code that is as easy to understand as if it were written in a pure functional programming style, even though it uses multiple threads, mutable state, thread preemption, and even thread abortion. Even better, concurrent composition and task canceling provide significant program structuring benefits that allow a clean decomposition and task separation in the solver.
Error Credits: Resourceful Reasoning about Error Bounds for Higher-Order Probabilistic Programs
Authors: Aguirre Alejandro , Haselwarter Philipp G. , de Medeiros Markus , Li Kwing Hei , Gregersen Simon Oddershede , Tassarotti Joseph , Birkedal Lars
Published: August 2024

Probabilistic programs often trade accuracy for efficiency, and thus

may, with a small probability, return an incorrect result.

It is important to obtain precise bounds for

the probability of these errors, but existing verification approaches have limitations that

lead to error probability bounds that are excessively coarse, or only apply to first-order programs.

In this paper we present Eris, a higher-order separation logic for proving

error probability bounds for probabilistic programs written in an expressive higher-order language.

Our key novelty is the introduction of error credits, a separation logic resource

that tracks an upper bound on the probability that a program returns an erroneous result.

By representing error bounds as a resource,

we recover the benefits of separation logic, including compositionality,

modularity, and dependency between errors and program terms, allowing

for more precise specifications. Moreover, we enable novel reasoning principles

such as expectation-preserving error composition, amortized error reasoning,

and error induction.

We illustrate the advantages of our approach by proving amortized error

bounds on a range of examples, including collision probabilities

in hash functions, which allow us to write

more modular specifications for data structures that use them as clients. We

also use our logic to prove correctness and almost-sure termination of

rejection sampling algorithms. All of our results have been mechanized

in the Coq proof assistant using the Iris separation logic framework and

the Coquelicot real analysis library.
Example-Based Reasoning about the Realizability of Polymorphic Programs
Authors: Mulleners Niek , Jeuring Johan , Heeren Bastiaan
Published: August 2024

Parametricity states that polymorphic functions behave the same regardless of how they are instantiated. When developing polymorphic programs, Wadler’s free theorems can serve as
free specifications
, which can turn otherwise partial specifications into total ones, and can make otherwise realizable specifications
unrealizable
. This is of particular interest to the field of program synthesis, where the unrealizability of a specification can be used to prune the search space. In this paper, we focus on the interaction between parametricity, input-output examples, and sketches. Unfortunately, free theorems introduce universally quantified functions that make automated reasoning difficult. Container morphisms provide an alternative representation for polymorphic functions that captures parametricity in a more manageable way. By using a translation to the container setting, we show how reasoning about the realizability of polymorphic programs with input-output examples can be automated.
Snapshottable Stores
Authors: Allain Clément , Clément Basile , Moine Alexandre , Scherer Gabriel
Published: August 2024

We say that an imperative data structure is
snapshottable
or
supports snapshots
if we can efficiently capture its current state, and restore a previously captured state to become the current state again. This is useful, for example, to implement backtracking search processes that update the data structure during search. Inspired by a data structure proposed in 1978 by Baker, we present a
snapshottable store
, a bag of mutable references that supports snapshots. Instead of capturing and restoring an array, we can capture an arbitrary set of references (of any type) and restore all of them at once. This snapshottable store can be used as a building block to support snapshots for arbitrary data structures, by simply replacing all mutable references in the data structure by our store references. We present use-cases of a snapshottable store when implementing type-checkers and automated theorem provers. Our implementation is designed to provide a very low overhead over normal references, in the common case where the capture/restore operations are infrequent. Read and write in store references are essentially as fast as in plain references in most situations, thanks to a key optimisation we call
record elision
. In comparison, the common approach of replacing references by integer indices into a persistent map incurs a logarithmic overhead on reads and writes, and sophisticated algorithms typically impose much larger constant factors. The implementation, which is inspired by Baker’s and the OCaml implementation of persistent arrays by Conchon and Filliâtre, is both fairly short and very hard to understand: it relies on shared mutable state in subtle ways. We provide a mechanized proof of correctness of its core using the Iris framework for the Coq proof assistant.
Oxidizing OCaml with Modal Memory Management
Authors: Lorenzen Anton , White Leo , Dolan Stephen , Eisenberg Richard A. , Lindley Sam
Published: August 2024

Programmers can often improve the performance of their programs by reducing heap allocations: either by allocating on the stack or reusing existing memory in-place. However, without safety guarantees, these optimizations can easily lead to use-after-free errors and even type unsoundness. In this paper, we present a design based on
modes
which allows programmers to safely reduce allocations by using stack allocation and in-place updates of immutable structures. We focus on three mode axes: affinity, uniqueness and locality. Modes are fully backwards compatible with existing OCaml code and can be completely inferred. Our work makes manual memory management in OCaml safe and convenient and charts a path towards bringing the benefits of Rust to OCaml.
Closure-Free Functional Programming in a Two-Level Type Theory
Authors: Kovács András
Published: August 2024

Many abstraction tools in functional programming rely heavily on general-purpose compiler optimization to achieve adequate performance. For example, monadic binding is a higher-order function which yields runtime closures in the absence of sufficient compile-time inlining and beta-reductions, thereby significantly degrading performance. In current systems such as the Glasgow Haskell Compiler, there is no strong guarantee that general-purpose optimization can eliminate abstraction overheads, and users only have indirect and fragile control over code generation through inlining directives and compiler options. We propose a two-stage language to simultaneously get strong guarantees about code generation and strong abstraction features. The object language is a simply-typed first-order language which can be compiled without runtime closures. The compile-time language is a dependent type theory. The two are integrated in a two-level type theory. We demonstrate two applications of the system. First, we develop monads and monad transformers. Here, abstraction overheads are eliminated by staging and we can reuse almost all definitions from the existing Haskell ecosystem. Second, we develop pull-based stream fusion. Here we make essential use of dependent types to give a concise definition of a
concatMap
operation with guaranteed fusion. We provide an Agda implementation and a typed Template Haskell implementation of these developments.
Parallel Algebraic Effect Handlers
Authors: Xie Ningning , Johnson Daniel D. , Maclaurin Dougal , Paszke Adam
Published: August 2024

Algebraic effect handlers support composable and structured control-flow abstraction. However, existing designs of algebraic effects often require effects to be executed sequentially. This paper studies parallel algebraic effect handlers. In particular, we formalize λ

p

, a lambda calculus which models two key features, effect handlers and parallelizable computations, the latter of which takes the form of a for expression, inspired by the Dex programming language. We present various interesting examples expressible in our calculus. To show that our design can be implemented in a type-safe way, we present a higher-order polymorphic lambda calculus F

p

that extends λ

p

with a lightweight value dependent type system, and prove that F

p

preserves the semantics of λ

p

and enjoys syntactic type soundness. Lastly, we provide an implementation of the language design as a Haskell library, which mirrors both λ

p

and F

p

and reveals new connections to free applicative functors. All examples presented can be encoded in the Haskell implementation. We believe this paper is the first to study the combination of user-defined effect handlers and parallel computations, and it is our hope that it provides a basis for future designs and implementations of parallel algebraic effect handlers.
CCLemma: E-Graph Guided Lemma Discovery for Inductive Equational Proofs
Authors: Kurashige Cole , Ji Ruyi , Giridharan Aditya , Barbone Mark , Noor Daniel , Itzhaky Shachar , Jhala Ranjit , Polikarpova Nadia
Published: August 2024

The problem of automatically proving the equality

of terms over recursive functions and

inductive data types is challenging,

as such proofs often require auxiliary lemmas

which must themselves be proven.

Previous attempts at lemma discovery compromise

on either efficiency or efficacy.
Goal-directed
approaches

are fast but limited in expressiveness,

as they can only discover auxiliary lemmas which

entail their goals.
Theory exploration
approaches

are expressive but inefficient,

as they exhaustively enumerate candidate lemmas.

We introduce
e-graph guided lemma discovery
,

a new approach to finding equational proofs

that makes theory exploration goal-directed.

We accomplish this by using e-graphs and equality saturation to

efficiently construct and compactly represent

the space of
all
goal-oriented proofs.

This allows us to explore only those auxiliary

lemmas
guaranteed
to help make progress

on some of these proofs.

We implemented our method in a new prover

called CCLemma and compared it with three state-of-the-art provers

across a variety of benchmarks.

CCLemma performs consistently well on two standard benchmarks

and additionally solves 50% more problems than the next best tool

on a new challenging set.
Call-by-Unboxed-Value
Authors: Downen Paul
Published: August 2024

Call-By-Push-Value has famously subsumed both call-by-name and call-by-value by decomposing programs along the axis of "values" versus "computations." Here, we introduce Call-By-Unboxed-Value which further decomposes programs along an orthogonal axis separating "atomic" versus "complex." As the name suggests, these two dimensions make it possible to express the representations of values as boxed or unboxed, so that functions pass unboxed values as inputs and outputs. More importantly, Call-By-Unboxed-Value allows for an unrestricted mixture of polymorphism and unboxed types, giving a foundation for studying compilation techniques for polymorphism based on representation irrelevance. In this regard, we use Call-By-Unboxed-Value to formalize representation polymorphism independently of types; for the first time compiling untyped representation-polymorphic code, while nonetheless preserving types all the way to the machine.
Comparison of analysis strategies to assess sex differences in microvascular reperfusion using near-infrared spectroscopy
Authors: Landers-Ramos Rian Q. , McCully Kevin K. , Knuth Nicolas D.
Published: August 2024

Sex differences in near-infrared spectroscopy (NIRS)-based microvascular reperfusion have been previously reported. We found that greater adipose tissue thickness in females reduces kinetic measures of NIRS-based microvascular reperfusion. Sex differences are eliminated when performing an adipose tissue thickness correction, when the NIRS signal range is accounted for, or when adipose tissue thickness is similar between sexes. This highlights the importance of considering factors that affect NIRS signals, such as adipose tissue thickness, when drawing comparisons between groups.
Persistent physiological benefits from doping? Ethical implications for sports integrity
Authors: Valenzuela Pedro L. , Sitko Sebastian , Pitsiladis Yannis
Published: August 2024

The effects of some widely abused doping substances such as anabolic androgenic steroids (AAS) on performance are well documented, particularly in the short term, and the use of these substances is banned by various sporting authorities, with athletes sanctioned from competing for up to 4 years. However, controversy exists on whether residual physiological effects of some doping practices could persist even years after discontinuation, granting unfair advantages to athletes long after sanctions have been served. Particularly, in support of the so-called muscle memory theory, growing evidence in both animals and humans suggests that AAS administration could exert long-term effects at the muscle level, notably a higher number of myonuclei. This effect could enhance retraining/muscle remodeling capacity long after AAS cessation, thus supposing an advantage for doped athletes even +4 years after doping practices have been discontinued. If confirmed, the persistence of physiological improvements resulting from past doping practices raises serious ethical concerns in the sports field and opens the door to lifelong sanctions.
Figure S3 from Serine Depletion Promotes Antitumor Immunity by Activating Mitochondrial DNA-Mediated cGAS-STING Signaling
Authors: Saha Suchandrima , Ghosh Monisankar , Li Jinyu , Wen Asher , Galluzzi Lorenzo , Martinez Luis A. , Montrose David C.
Published: August 2024

Figure S3
Supplementary Movie 2 from Integration of Clinical Trial Spatial Multiomics Analysis and Virtual Clinical Trials Enables Immunotherapy Response Prediction and Biomarker Discovery
Authors: Zhang Shuming , Deshpande Atul , Verma Babita K. , Wang Hanwen , Mi Haoyang , Yuan Long , Ho Won Jin , Jaffee Elizabeth M. , Zhu Qingfeng , Anders Robert A. , Yarchoan Mark , Kagohara Luciane T. , Fertig Elana J. , Popel Aleksander S.
Published: August 2024

Supplementary Movie 2
Supplementary Fig. S8 from FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis
Authors: Su Dan , Wang Ruobing , Chen Guangyu , Ding Chen , Liu Yueze , Tao Jinxin , Wang Yuanyang , Qiu Jiangdong , Luo Wenhao , Weng Guihu , Yang Gang , Zhang Taiping
Published: August 2024

Supplementary Fig. S8
Data from CDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer
Authors: Li Wei , Guo Feng , Zeng Ruijiang , Liang Huaiyuan , Wang Yinhuai , Xiong Wei , Wu Heshui , Yang Chunguang , Jin Xin
Published: August 2024

Abstract
The efficacy of immunotherapy in patients with prostate cancer is limited due to the “cold” tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis is involved in innate immunity and has been increasingly recognized as a candidate target for cancer immunotherapy. Here, we found that treatment with CDK4/6 inhibitors stimulates the STING pathway and enhances the antitumor effect of STING agonists in prostate cancer. Mechanistically, CDK4/6 phosphorylated TBK1 at S527 to inactivate the STING signaling pathway independent of RB1 in prostate cancer cells. CDK4/6-mediated phosphorylation of RB1 at S249/T252 also induced the interaction of RB1 with TBK1 to diminish the phosphorylation of TBK1 at S172, which suppressed STING pathway activation. Overall, this study showed that CDK4/6 suppresses the STING pathway through RB1-dependent and RB1-independent pathways, indicating that CDK4/6 inhibition could be a potential strategy to overcome immunosuppression in prostate cancer.

Significance: Inhibiting CDK4/6 activates STING-TBK1-IRF3 signaling in prostate cancer by regulating TBK1 phosphorylation, suggesting that the combination of CDK4/6 inhibitors and STING agonists could be an effective approach to stimulate innate immunity.
Data from Integration of Clinical Trial Spatial Multiomics Analysis and Virtual Clinical Trials Enables Immunotherapy Response Prediction and Biomarker Discovery
Authors: Zhang Shuming , Deshpande Atul , Verma Babita K. , Wang Hanwen , Mi Haoyang , Yuan Long , Ho Won Jin , Jaffee Elizabeth M. , Zhu Qingfeng , Anders Robert A. , Yarchoan Mark , Kagohara Luciane T. , Fertig Elana J. , Popel Aleksander S.
Published: August 2024

Abstract
Due to the lack of treatment options, there remains a need to advance new therapeutics in hepatocellular carcinoma (HCC). The traditional approach moves from initial molecular discovery through animal models to human trials to advance novel systemic therapies that improve treatment outcomes for patients with cancer. Computational methods that simulate tumors mathematically to describe cellular and molecular interactions are emerging as promising tools to simulate the impact of therapy entirely in silico, potentially greatly accelerating delivery of new therapeutics to patients. To facilitate the design of dosing regimens and identification of potential biomarkers for immunotherapy, we developed a new computational model to track tumor progression at the organ scale while capturing the spatial heterogeneity of the tumor in HCC. This computational model of spatial quantitative systems pharmacology was designed to simulate the effects of combination immunotherapy. The model was initiated using literature-derived parameter values and fitted to the specifics of HCC. Model validation was done through comparison with spatial multiomics data from a neoadjuvant HCC clinical trial combining anti-PD1 immunotherapy and a multitargeted tyrosine kinase inhibitor cabozantinib. Validation using spatial proteomics data from imaging mass cytometry demonstrated that closer proximity between CD8 T cells and macrophages correlated with nonresponse. We also compared the model output with Visium spatial transcriptomics profiling of samples from posttreatment tumor resections in the clinical trial and from another independent study of anti-PD1 monotherapy. Spatial transcriptomics data confirmed simulation results, suggesting the importance of spatial patterns of tumor vasculature and TGFβ in tumor and immune cell interactions. Our findings demonstrate that incorporating mathematical modeling and computer simulations with high-throughput spatial multiomics data provides a novel approach for patient outcome prediction and biomarker discovery.

Significance: Incorporating mathematical modeling and computer simulations with high-throughput spatial multiomics data provides an effective approach for patient outcome prediction and biomarker discovery.
Supplementary Table S8 from A Novel Approach to Quantify Heterogeneity of Intrahepatic Cholangiocarcinoma: The Hidden-Genome Classifier
Authors: Song Yi , Boerner Thomas , Drill Esther , Shin Paul , Kumar Sandeep , Sigel Carlie , Cercek Andrea , Kemeny Nancy , Abou-Alfa Ghassan , Iacobuzio-Donahue Christine , Cowzer Darren , Schultz Nikolaus , Walch Henry , Balachandran Vinod , Groot Koerkamp Bas , Kingham Peter , Soares Kevin , Wei Alice , D’Angelica Michael , Drebin Jeffrey , Chandwani Rohit , Harding James J. , Jarnagin William
Published: August 2024

Histologic subtypes of biliary-class and HCC-class intrahepatic cholangiocarcinoma (IHC).
Supplementary Figure S9 from Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Nonsmokers and Tobacco Smokers
Authors: Dalal Bhavik , Tada Takeshi , Patel Daxesh P. , Pine Sharon R. , Khan Mohammed , Oike Takahiro , Kanke Yasuyuki , Parker Amelia L. , Haznadar Majda , Toulabi Leila , Krausz Kristopher W. , Robles Ana I. , Bowman Elise D. , Gonzalez Frank J. , Harris Curtis C.
Published: August 2024

Cox proportional analysis for factors associated with survival
Supplementary Table S2 from A Novel Approach to Quantify Heterogeneity of Intrahepatic Cholangiocarcinoma: The Hidden-Genome Classifier
Authors: Song Yi , Boerner Thomas , Drill Esther , Shin Paul , Kumar Sandeep , Sigel Carlie , Cercek Andrea , Kemeny Nancy , Abou-Alfa Ghassan , Iacobuzio-Donahue Christine , Cowzer Darren , Schultz Nikolaus , Walch Henry , Balachandran Vinod , Groot Koerkamp Bas , Kingham Peter , Soares Kevin , Wei Alice , D’Angelica Michael , Drebin Jeffrey , Chandwani Rohit , Harding James J. , Jarnagin William
Published: August 2024

Prevalence of genes altered in 10% or more cases.
Supplementary Table S1 from A Novel Approach to Quantify Heterogeneity of Intrahepatic Cholangiocarcinoma: The Hidden-Genome Classifier
Authors: Song Yi , Boerner Thomas , Drill Esther , Shin Paul , Kumar Sandeep , Sigel Carlie , Cercek Andrea , Kemeny Nancy , Abou-Alfa Ghassan , Iacobuzio-Donahue Christine , Cowzer Darren , Schultz Nikolaus , Walch Henry , Balachandran Vinod , Groot Koerkamp Bas , Kingham Peter , Soares Kevin , Wei Alice , D’Angelica Michael , Drebin Jeffrey , Chandwani Rohit , Harding James J. , Jarnagin William
Published: August 2024

Genes (n = 341) common to all MSK-IMPACT panels.
Table 1 from Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
Authors: Saner Flurina A.M. , Takahashi Kazuaki , Budden Timothy , Pandey Ahwan , Ariyaratne Dinuka , Zwimpfer Tibor A. , Meagher Nicola S. , Fereday Sian , Twomey Laura , Pishas Kathleen I. , Hoang Therese , Bolithon Adelyn , Traficante Nadia , Alsop Kathryn , Christie Elizabeth L. , Kang Eun-Young , Nelson Gregg S. , Ghatage Prafull , Lee Cheng-Han , Riggan Marjorie J. , Alsop Jennifer , Beckmann Matthias W. , Boros Jessica , Brand Alison H. , Brooks-Wilson Angela , Carney Michael E. , Coulson Penny , Courtney-Brooks Madeleine , Cushing-Haugen Kara L. , Cybulski Cezary , El-Bahrawy Mona A. , Elishaev Esther , Erber Ramona , Gayther Simon A. , Gentry-Maharaj Aleksandra , Gilks C. Blake , Harnett Paul R. , Harris Holly R. , Hartmann Arndt , Hein Alexander , Hendley Joy , Hernandez Brenda Y. , Jakubowska Anna , Jimenez-Linan Mercedes , Jones Michael E. , Kaufmann Scott H. , Kennedy Catherine J. , Kluz Tomasz , Koziak Jennifer M. , Kristjansdottir Björg , Le Nhu D. , Lener Marcin , Lester Jenny , Lubiński Jan , Mateoiu Constantina , Orsulic Sandra , Ruebner Matthias , Schoemaker Minouk J. , Shah Mitul , Sharma Raghwa , Sherman Mark E. , Shvetsov Yurii B. , Soong T. Rinda , Steed Helen , Sukumvanich Paniti , Talhouk Aline , Taylor Sarah E. , Vierkant Robert A. , Wang Chen , Widschwendter Martin , Wilkens Lynne R. , Winham Stacey J. , Anglesio Michael S. , Berchuck Andrew , Brenton James D. , Campbell Ian , Cook Linda S. , Doherty Jennifer A. , Fasching Peter A. , Fortner Renée T. , Goodman Marc T. , Gronwald Jacek , Huntsman David G. , Karlan Beth Y. , Kelemen Linda E. , Menon Usha , Modugno Francesmary , Pharoah Paul D.P. , Schildkraut Joellen M. , Sundfeldt Karin , Swerdlow Anthony J. , Goode Ellen L. , DeFazio Anna , Köbel Martin , Ramus Susan J. , Bowtell David D.L. , Garsed Dale W.
Published: August 2024

Clinicopathologic characteristics and RB1 expression patterns across histotypes.
Supplementary Figures S1-S22 from Nivolumab with or without Ipilimumab Combined with Stereotactic Body Radiotherapy in Patients with Metastatic Biliary Tract Cancer: A Randomized Phase 2 Study
Authors: Markussen Alice , Johansen Julia S. , Larsen Finn O. , Theile Susann , Hasselby Jane P. , Willemoe Gro L. , Lorentzen Torben , Madsen Kasper , Høgdall Estrid , Poulsen Tim S. , Wilken Eva E. , Geertsen Poul , Behrens Claus P. , Svane Inge M. , Nielsen Dorte , Chen Inna M.
Published: August 2024

Supplementary Figure S1. CheckPAC study design Supplementary Figure S2. Best percentage change in target lesions from baseline in evaluable patients Supplementary Figure S3. Kaplan–Meier plot of PFS and OS in SBRT/nivolumab/ipilimumab-group (A, C) and SBRT/nivolumab-group (B, D) Supplementary Figure S4. Responder 1 Supplementary Figure S5. Responder 2 Supplementary Figure S6. Responder 3 Supplementary Figure S7. Responder 4 Supplementary Figure S8. Responder 5 Supplementary Figure S9. DOR for the five patients achieving partial response after SBRT/nivolumab/ipilimumab Supplementary Figure S10. TMB in patients who achieved clinical benefit (stable disease or partial response) compared to those with no clinical benefit (PD) Supplementary Figure S11. Distribution of PD-L1 expression according to response Supplementary Figure S12. Individual changes in CD3, CD8 and CD163 Supplementary Figure S13. Distribution of CD3, CB8, and CD163 at baseline and on treatment Supplementary Figure S14. Boxplots illustrating serum concentrations of CA 19-9 (A), CRP (B), IL-6 (C), IL-8 (D), and IL-17 (E) at baseline and during treatment Supplementary Figure S15. Individual changes in serum concentrations of CA 19-9 (A), CRP (B), IL-6 (C), IL-8 (D), and IL-17 (E) Supplementary Figure S16. Correlations between the circulating biomarkers CA 19-9, CRP, IL-6, IL-8, and IL-17 at baseline and during treatment Supplementary Figure S17. Kaplan-Meier analysis of progression free survival according to baseline serum concentrations of CA 19-9 (A), CRP (B), IL-6 (C), IL-8 (D), and IL-17 (E) Supplementary Figure S18. Kaplan-Meier analysis of overall survival according to baseline serum concentrations of CA 19-9 (A), CRP (B), IL-6 (C), IL-8 (D), and IL-17 (E) Supplementary Figure S19. Kaplan-Meier analysis of overall survival according to serum concentrations 2 months after start of treatment of CA 19-9 (A), CRP (B), IL-6 (C), IL-8 (D), and IL-17 (E) Supplementary Figure S20. Kaplan-Meier analysis of overall survival according to changes in serum concentrations of CA 19-9 (A), CRP (B), IL-6 (C), IL-8 (D), and IL-17 (E) Supplementary Figure S21. Forest plot of OS and HR from the univariate Cox regression analysis Supplementary Figure S22. Forest plot with OS and HR based on multivariate Cox regression analysis
Supplementary Table S19 from Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
Authors: Saner Flurina A.M. , Takahashi Kazuaki , Budden Timothy , Pandey Ahwan , Ariyaratne Dinuka , Zwimpfer Tibor A. , Meagher Nicola S. , Fereday Sian , Twomey Laura , Pishas Kathleen I. , Hoang Therese , Bolithon Adelyn , Traficante Nadia , Alsop Kathryn , Christie Elizabeth L. , Kang Eun-Young , Nelson Gregg S. , Ghatage Prafull , Lee Cheng-Han , Riggan Marjorie J. , Alsop Jennifer , Beckmann Matthias W. , Boros Jessica , Brand Alison H. , Brooks-Wilson Angela , Carney Michael E. , Coulson Penny , Courtney-Brooks Madeleine , Cushing-Haugen Kara L. , Cybulski Cezary , El-Bahrawy Mona A. , Elishaev Esther , Erber Ramona , Gayther Simon A. , Gentry-Maharaj Aleksandra , Gilks C. Blake , Harnett Paul R. , Harris Holly R. , Hartmann Arndt , Hein Alexander , Hendley Joy , Hernandez Brenda Y. , Jakubowska Anna , Jimenez-Linan Mercedes , Jones Michael E. , Kaufmann Scott H. , Kennedy Catherine J. , Kluz Tomasz , Koziak Jennifer M. , Kristjansdottir Björg , Le Nhu D. , Lener Marcin , Lester Jenny , Lubiński Jan , Mateoiu Constantina , Orsulic Sandra , Ruebner Matthias , Schoemaker Minouk J. , Shah Mitul , Sharma Raghwa , Sherman Mark E. , Shvetsov Yurii B. , Soong T. Rinda , Steed Helen , Sukumvanich Paniti , Talhouk Aline , Taylor Sarah E. , Vierkant Robert A. , Wang Chen , Widschwendter Martin , Wilkens Lynne R. , Winham Stacey J. , Anglesio Michael S. , Berchuck Andrew , Brenton James D. , Campbell Ian , Cook Linda S. , Doherty Jennifer A. , Fasching Peter A. , Fortner Renée T. , Goodman Marc T. , Gronwald Jacek , Huntsman David G. , Karlan Beth Y. , Kelemen Linda E. , Menon Usha , Modugno Francesmary , Pharoah Paul D.P. , Schildkraut Joellen M. , Sundfeldt Karin , Swerdlow Anthony J. , Goode Ellen L. , DeFazio Anna , Köbel Martin , Ramus Susan J. , Bowtell David D.L. , Garsed Dale W.
Published: August 2024

Supplementary Table S19. Relative expression of BRCA1 and RB1 by qPCR in AOCS30 CRISPR knockout model.
Supplementary Figure S7 from Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
Authors: Saner Flurina A.M. , Takahashi Kazuaki , Budden Timothy , Pandey Ahwan , Ariyaratne Dinuka , Zwimpfer Tibor A. , Meagher Nicola S. , Fereday Sian , Twomey Laura , Pishas Kathleen I. , Hoang Therese , Bolithon Adelyn , Traficante Nadia , Alsop Kathryn , Christie Elizabeth L. , Kang Eun-Young , Nelson Gregg S. , Ghatage Prafull , Lee Cheng-Han , Riggan Marjorie J. , Alsop Jennifer , Beckmann Matthias W. , Boros Jessica , Brand Alison H. , Brooks-Wilson Angela , Carney Michael E. , Coulson Penny , Courtney-Brooks Madeleine , Cushing-Haugen Kara L. , Cybulski Cezary , El-Bahrawy Mona A. , Elishaev Esther , Erber Ramona , Gayther Simon A. , Gentry-Maharaj Aleksandra , Gilks C. Blake , Harnett Paul R. , Harris Holly R. , Hartmann Arndt , Hein Alexander , Hendley Joy , Hernandez Brenda Y. , Jakubowska Anna , Jimenez-Linan Mercedes , Jones Michael E. , Kaufmann Scott H. , Kennedy Catherine J. , Kluz Tomasz , Koziak Jennifer M. , Kristjansdottir Björg , Le Nhu D. , Lener Marcin , Lester Jenny , Lubiński Jan , Mateoiu Constantina , Orsulic Sandra , Ruebner Matthias , Schoemaker Minouk J. , Shah Mitul , Sharma Raghwa , Sherman Mark E. , Shvetsov Yurii B. , Soong T. Rinda , Steed Helen , Sukumvanich Paniti , Talhouk Aline , Taylor Sarah E. , Vierkant Robert A. , Wang Chen , Widschwendter Martin , Wilkens Lynne R. , Winham Stacey J. , Anglesio Michael S. , Berchuck Andrew , Brenton James D. , Campbell Ian , Cook Linda S. , Doherty Jennifer A. , Fasching Peter A. , Fortner Renée T. , Goodman Marc T. , Gronwald Jacek , Huntsman David G. , Karlan Beth Y. , Kelemen Linda E. , Menon Usha , Modugno Francesmary , Pharoah Paul D.P. , Schildkraut Joellen M. , Sundfeldt Karin , Swerdlow Anthony J. , Goode Ellen L. , DeFazio Anna , Köbel Martin , Ramus Susan J. , Bowtell David D.L. , Garsed Dale W.
Published: August 2024

Supplementary Figure S7. Genomic and clinical characteristics by combined homologous recombination deficiency and RB1 status.
Supplementary Figure S3 from Preclinical Development of CAR T Cells with Antigen-Inducible IL18 Enforcement to Treat GD2-Positive Solid Cancers
Authors: Fischer-Riepe Lena , Kailayangiri Sareetha , Zimmermann Katharina , Pfeifer Rita , Aigner Michael , Altvater Bianca , Kretschmann Sascha , Völkl Simon , Hartley Jordan , Dreger Celine , Petry Katja , Bosio Andreas , von Döllen Angelika , Hartmann Wolfgang , Lode Holger , Görlich Dennis , Mackensen Andreas , Jungblut Melanie , Schambach Axel , Abken Hinrich , Rossig Claudia
Published: August 2024

GD2IL18CART tolerability experiment
Supplementary Table S3 from Spatially Informed Gene Signatures for Response to Immunotherapy in Melanoma
Authors: Aung Thazin N. , Warrell Jonathan , Martinez-Morilla Sandra , Gavrielatou Niki , Vathiotis Ioannis , Yaghoobi Vesal , Kluger Harriet M. , Gerstein Mark , Rimm David L.
Published: August 2024

Supplementary Table S3. Survival analysis of both discovery and validation cohorts. To establish the optimal cutpoint, median, tertile and tertile (1st vs. 3rd) were used. The optimal observed cutpoint was selected to test the association overall survival (days) from start of immunotherapy in the validation cohort.
Supplementary Figure S6 from Spatially Informed Gene Signatures for Response to Immunotherapy in Melanoma
Authors: Aung Thazin N. , Warrell Jonathan , Martinez-Morilla Sandra , Gavrielatou Niki , Vathiotis Ioannis , Yaghoobi Vesal , Kluger Harriet M. , Gerstein Mark , Rimm David L.
Published: August 2024

Supplementary Figure S6. Compartment-level deconvolution of bulk mRNA for validation of spatial signatures.
Supplementary Table S3 from A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors
Authors: Takaki Emiri O. , Kiyono Kunihiko , Obuchi Yutaka , Yamauchi Takeshi , Watanabe Takashi , Matsumoto Hideki , Karimine Miho , Kuniyoshi Yuki , Nishikori Shingo , Yokoyama Fumiharu , Nishimori Hikaru , Nabeshima Hiroshi , Nakamura Kazuhide
Published: August 2024

Supplementary Table 3. Inhibition of phosphodiesterase activity by OPB-171775.
Data from Intraperitoneal Nivolumab after Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: A Phase I Study with Expansion Cohort
Authors: Corbaux Pauline , Freyer Gilles , Glehen Olivier , You Benoît , Bakrin Naoual , Gelot Audrey , Dayde David , Sajous Christophe , Piffoux Max , Péron Julien , Lescuyer Gaelle , Payen Lea , Kepenekian Vahan
Published: August 2024

AbstractPurpose:
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761).
Patients and Methods:
Patients received IP nivolumab (0.5, 1, or 3 mg/kg) using a 3 + 3 dose-escalation design, starting 5 to 7 days after CRS and HIPEC. Four IP Q2W (once every 2 weeks) nivolumab infusions were planned. The primary objective was to demonstrate the feasibility of IP nivolumab based on dose-limiting toxicity. Secondary objectives were to assess changes in tolerance of CRS and HIPEC.
Results:
A total of 17 patients were enrolled including 10 patients in the dose escalation and 7 patients in the expansion phase. No dose-limiting toxicity was observed at any dose level in the 9 evaluable patients. Six of the 17 patients (35%) did not complete all planned infusions: 4 (23.5%) due to peritoneal catheter complications and 2 (11.8%) due to early progression. No procedure-related deaths occurred. Eleven patients (65%) experienced serious adverse events (SAE), mainly transitory grade 3 to 4 transaminase elevations (6/11) and surgery-related (9/11). Four SAEs were related to the peritoneal catheter and two to HIPEC. No SAEs/grade 3 to 4 adverse events related to IP nivolumab occurred.
Conclusions:
This is the first study demonstrating the feasibility of IP nivolumab in patients with relapsed advanced ovarian cancer. Further investigation at 3 mg/kg is warranted.
Data from Missense Mutations in Myc Box I Influence Nucleocytoplasmic Transport to Promote Leukemogenesis
Authors: Arthur Nancy B.J. , Christensen Keegan A. , Mannino Kathleen , Ruzinova Marianna B. , Kumar Ashutosh , Gruszczynska Agata , Day Ryan B. , Erdmann-Gilmore Petra , Mi Yiling , Sprung Robert , York Conner R. , Townsend Robert R. , Spencer David H. , Sykes Stephen M. , Ferraro Francesca
Published: August 2024

AbstractPurpose:
Somatic missense mutations in the phosphodegron domain of the MYC gene (MYC Box I or MBI) are detected in the dominant clones of a subset of patients with acute myeloid leukemia (AML), but the mechanisms by which they contribute to AML are unknown.
Experimental Design:
To investigate the effects of MBI MYC mutations on hematopoietic cells, we employed a multi-omic approach to systematically compare the cellular and molecular consequences of expressing oncogenic doses of wild type, threonine-58 and proline-59 mutant MYC proteins in hematopoietic cells, and we developed a knockin mouse harboring the germline MBI mutation p.T58N in the Myc gene.
Results:
Both wild-type and MBI mutant MYC proteins promote self-renewal programs and expand highly selected subpopulations of progenitor cells in the bone marrow. Compared with their wild-type counterparts, mutant cells display decreased cell death and accelerated leukemogenesis in vivo, changes that are recapitulated in the transcriptomes of human AML-bearing MYC mutations. The mutant phenotypes feature decreased stability and translation of mRNAs encoding proapoptotic and immune-regulatory genes, increased translation of RNA binding proteins and nuclear export machinery, and distinct nucleocytoplasmic RNA profiles. MBI MYC mutant proteins also show a higher propensity to aggregate in perinuclear regions and cytoplasm. Like the overexpression model, heterozygous p.T58N knockin mice displayed similar changes in subcellular MYC localization, progenitor expansion, transcriptional signatures, and develop hematopoietic tumors.
Conclusions:
This study uncovers that MBI MYC mutations alter RNA nucleocytoplasmic transport mechanisms to contribute to the development of hematopoietic malignancies.
Table 3 from Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC
Authors: Nakazawa Mari , Fang Mike , Vong Tyrus , Zorzi Jane , Griffith Paige , Anders Robert A. , Oshima Kiyoko , Kim Amy K. , Laurin Jacqueline , Lafaro Kelly J. , Shubert Christopher R. , Burns William R. , He Jin , Burkhart Richard A. , Philosophe Benjamin , Meyer Jeffrey , Liddell Robert P. , Georgiades Christos , Hong Kelvin , Ho Won Jin , Baretti Marina , Strauss Alexandra T. , Yarchoan Mark
Published: August 2024

Pathologic outcomes at time of surgery in patients who underwent ICI-based neoadjuvant therapy or upfront resection for HCC
Table 1 from Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC
Authors: Nakazawa Mari , Fang Mike , Vong Tyrus , Zorzi Jane , Griffith Paige , Anders Robert A. , Oshima Kiyoko , Kim Amy K. , Laurin Jacqueline , Lafaro Kelly J. , Shubert Christopher R. , Burns William R. , He Jin , Burkhart Richard A. , Philosophe Benjamin , Meyer Jeffrey , Liddell Robert P. , Georgiades Christos , Hong Kelvin , Ho Won Jin , Baretti Marina , Strauss Alexandra T. , Yarchoan Mark
Published: August 2024

Baseline characteristics of patients who underwent ICI-based neoadjuvant therapy or upfront resection for HCC
Data from Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC
Authors: Nakazawa Mari , Fang Mike , Vong Tyrus , Zorzi Jane , Griffith Paige , Anders Robert A. , Oshima Kiyoko , Kim Amy K. , Laurin Jacqueline , Lafaro Kelly J. , Shubert Christopher R. , Burns William R. , He Jin , Burkhart Richard A. , Philosophe Benjamin , Meyer Jeffrey , Liddell Robert P. , Georgiades Christos , Hong Kelvin , Ho Won Jin , Baretti Marina , Strauss Alexandra T. , Yarchoan Mark
Published: August 2024

Abstract
Surgical resection for localized hepatocellular carcinoma (HCC) is typically reserved for a minority of patients with favorable tumor features and anatomy. Neoadjuvant immunotherapy can expand the number of patients who are candidates for surgical resection and potentially reduce the chance for recurrence, but its role in HCC not defined. We retrospectively examined the outcomes of patients who underwent surgical resection for HCC at the Johns Hopkins Hospital and compared the clinical outcomes of patients who received neoadjuvant immunotherapy with those who underwent upfront resection. The clinical cohort included a total of 92 patients, 36 of whom received neoadjuvant immune checkpoint inhibitor (ICI)-based treatment. A majority of patients (61.1%) who received neoadjuvant ICI–based therapy were outside of standard resectability criteria and were more likely to have features known to confer risk of disease recurrence, including α-fetoprotein ≥ 400 ng/mL (P = 0.02), tumor diameter ≥ 5 cm (P = 0.001), portal vein invasion (P < 0.001), and multifocality (P < 0.001). Patients who received neoadjuvant immunotherapy had similar rates of margin-negative resection (P = 0.47) and recurrence-free survival (RFS) as those who underwent upfront surgical resection (median RFS 44.8 months compared with 49.3 months, respectively, log-rank P = 0.66). There was a nonsignificant trend toward superior RFS in the subset of patients with a pathologic response (tumor necrosis ≥ 70%) with neoadjuvant immunotherapy. Neoadjuvant ICI-based therapy may allow high-risk patients, including those who are outside traditional resectability criteria, to achieve comparable clinical outcomes with those who undergo upfront resection.
Significance:
Surgical resection for localized HCC is typically only reserved for those with solitary tumors without vascular invasion. In this retrospective analysis, we show that neoadjuvant immunotherapy may allow high-risk patients, including those who are outside of standard resection criteria, to undergo successful margin-negative resection and achieve comparable long-term clinical outcomes compared with upfront resection. These findings highlight need for prospective studies on neoadjuvant immunotherapy in HCC.