bluuebunny/crossref_metadata_2025 huggingface dataset:
LoRe: A Programming Model for Verifiably Safe Local-first Software
Authors: Haas Julian , Mogk Ragnar , Yanakieva Elena , Bieniusa Annette , Mezini Mira
Published: December 2023

Local-first software manages and processes private data locally while still enabling collaboration between multiple parties connected via partially unreliable networks. Such software typically involves interactions with users and the execution environment (the outside world). The unpredictability of such interactions paired with their decentralized nature make reasoning about the correctness of local-first software a challenging endeavor. Yet, existing solutions to develop local-first software do not provide support for automated safety guarantees and instead expect developers to reason about concurrent interactions in an environment with unreliable network conditions.

We propose
LoRe
, a programming model and compiler that automatically verifies developer-supplied safety properties for local-first applications.
LoRe
combines the declarative data flow of reactive programming with static analysis and verification techniques to precisely determine concurrent interactions that violate safety invariants and to selectively employ strong consistency through coordination where required. We propose a formalized proof principle and demonstrate how to automate the process in a prototype implementation that outputs verified executable code. Our evaluation shows that
LoRe
simplifies the development of safe local-first software when compared to state-of-the-art approaches and that verification times are acceptable.
Radial Nerve Palsy Associated with Humeral Shaft Fractures in Children
Authors: Łukasz Wiktor , Ryszard Tomaszewski , Maria Damps
Published: December 2023

Background. This is the first systematic review of the relationship between humeral shaft fractures and radial nerve palsy in children. The present comprehensive review is aimed at identifying important clinical findings between humeral diaphysis fractures and radial nerve injuries and assessing the effects of treatment. Methods. We searched electronic bibliographic databases, including PubMed, the Cochrane Library, Scopus, and Web of Knowledge, until March 2022. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and the patients, interventions, comparisons, outcomes guidelines. Results. We identified 23 original papers, of which 10 were eligible for further analysis. Cases of 32 young patients with radial nerve palsy were identified and analyzed. The prevalence of radial nerve palsy was 4.34% (eight cases out of 184 patients with humeral shaft fractures). The radial nerve was most often associated with a simple transverse fracture (12A3, 17 cases (65.4%)). Conclusions. Radial nerve injury in humeral shaft fractures in children is rare, with a frequency of 4.34%. We highly recommend early surgical nerve exploration with transverse fractures in the distal third segment combined with primary radial palsy. Furthermore, we recommend making thoughtful decisions regarding early nerve exploration in the Holstein–Lewis fractures. In addition, consideration of early surgical nerve exploration in fractures resulting from high‐energy trauma and open fractures despite their morphology is recommended.
Virtual Fatigue Behaviour Analysis of Coir Fibre-Reinforced PVC Composites
Authors: Venkatachalam Gopalan , Jayanthi Umapathy , Suja Arumugasamy , Gnanaaksaya Senthil , Aravindh Sampath , Velu Pitchumani Shenbaga , Balamurugan Kulendran , Gopal Rajendiran
Published: December 2023

PVC (polyvinyl chloride) is a tough polymer used in applications, including plumbing and construction materials. As natural fibre-reinforced composites have more advantages over conventional synthetic composites, this paper focuses on the fatigue analysis of PVC composite which is reinforced with coir fibre. The influences of three input parameters, namely, the size of the coir fibre, coir fibre content, and the chemicals that are used in the treatment of coir fibre on the fatigue life of the composite are examined. In the response surface model (RSM), Box-Behnken designs (BBD) are employed for the preparation/analysis/optimization of the samples. ANSYS software is used to perform the fatigue analysis of different samples containing various combinations of the parameters. To determine the effects of various input parameters on the fatigue behaviour of composites, ANOVA is employed to determine their optimal levels. Regression equations are established to determine the fatigue limit. When treated with triethoxy(ethyl)silane, coir with a concentration of 6 wt.% and a particle size of 75 μm exhibits a maximum fatigue limit of 2.819 MPa.
The Effect of a Combined Mindfulness and Yoga Intervention on Soldier Mental Health in Basic Combat Training: A Cluster Randomized Controlled Trial
Authors: Nassif Thomas H. , Gutierrez Ian A. , Smith Carl D. , Jha Amishi P. , Adler Amy B.
Published: December 2023

Background. Depression, anxiety, and sleep problems are prevalent in high-stress occupations including military service. While effective therapies are available, scalable preventive mental health care interventions are needed. This study examined the impact of a combined mindfulness and yoga intervention on the mental health of soldiers in Basic Combat Training (BCT). Methods. U.S. Army soldiers (

N
=
1,896

) were randomized by platoon to an intervention or training-as-usual condition. Soldiers in the intervention condition completed Mindfulness-Based Attention Training (MBAT), engaged in daily 15 min mindfulness practice, and participated in 30 minutes of hatha yoga 6 days per week. Surveys were administered at baseline (T1, prior to training), week 4 of BCT (T2), week 6 (T3), and week 9 (T4). Results. A significant time-by-condition interaction predicting positive screens for depression found that screens decreased at a faster rate from T1 to T4 in the intervention condition (-12.6%) compared to training-as-usual (-7.2%) (

b
=
−
0.18

,

SE
=
0.07

,

p
=
0.028

). While positive anxiety screens decreased over time across conditions, the time-by-condition interaction found no significant differences in the rate of these decreases by condition (

b
=
0.09

,

SE
=
0.09

,

p
=
0.273

). A significant time-by-condition interaction predicting positive screens for sleep problems found that sleep problems decreased in the intervention condition (-1.4%) but increased in training-as-usual (2.0%) (

b
=
−
0.68

,

SE
=
0.16

,

p
=
0.027

). Conclusion. The mindfulness and yoga intervention was associated with a greater reduction in positive screens for depression and sleep problems among soldiers during high-stress training. Limitations include reliance on self-report and the inability to disaggregate the effects of mindfulness versus yoga. Mindfulness and yoga may enable personnel in high-stress occupations to sustain their mental health even in the context of significant psychological demands. This trial is registered with NCT05550610.
Failure Analysis of Tubing Collapse in a Gas Well
Authors: Zhao Jinlan , Tong Ke , Lei Junjie , Bai Xiaoliang , Li Dongfeng , Shen Zhaoxi , Qu Tingting , Li Xiaolong
Published: December 2023

The tubing used in a gas well rarely collapses and fails during applying annulus pressure. In this study, the failure causes of tubing collapse were analyzed by means of data verification, macroscopic observation, magnetic particle inspection, physical and chemical inspection, optical microscopy, and tubing collapse test. Mechanical analysis of the string and full‐scale physical simulation test simulating downhole working conditions. Finally, the verification analysis of the collapse test is carried out by the finite element analysis (FEA). The results showed that (1) the physical dimension, physical and chemical properties, and collapse resistance of this batch of tubing met the requirements of the tubing ordering technical standard. (2) Assuming that the well packer slip was unsealed and could slide freely, the mechanical theoretical analysis of collapsed tubing string and collapse test under simulated working condition load was carried out, which reproduced the load when the tubing collapsed. It can be seen from this that the packer did fail. (3) The FEA calculation results showed that when the external pressure was greater than 30.75 MPa, it would inevitably lead to collapse failure in case of packer unsealed. In conclusion, the root cause for the collapse failure of the 105th underground tubing string was that the packer lost its sealing function, resulting in an abnormal axial load. While under the action of external pressure, the tubing was overloaded and collapsed. It is recommended to carry out verification tests on the material performance of packer slip, the dimensional changes of packer tool outer diameter and inner diameter under actual well conditions, the creep behavior of packer seal, and the performance of shear pin under actual working conditions, especially in the well containing H2S, so as to prevent the pressure leakage of gas well annulus caused by packer unsealing and the reoccurrence of such downhole string collapse accidents. The first collapse test under simulated working condition load is conducted in this paper. Analyzing the collapse failure work and putting forward suggestions to effectively prevent similar failures from happening again are of great significance to the oilfield.
Serological Evidence and Coexposure of Selected Infections among Livestock Slaughtered at Eastern Cape Abattoirs in South Africa
Authors: Mazwi K. D. , Kolo F. B. , Jaja I. F. , Bokaba R. P. , Ngoshe Y. B. , Hassim A. , Neves L. , van Heerden H.
Published: December 2023

Zoonotic infections were investigated in a cross-sectional study on asymptomatic livestock slaughtered in abattoirs in the Eastern Cape. Antibodies against Brucella spp., Coxiella burnetii, Toxoplasma gondii, and the coexposure were investigated in sera using serological tests. A total of 565 animals comprising of 280 cattle, 200 sheep, and 85 pigs were screened using RBT, iELISA, CFT, and AMOS-PCR. The Mast® Toxoreagent test and iELISA were used for the detection of T. gondii and C. burnetii, respectively. The Brucella positivity based on at least two tests was 4.3% (12/280), 1.0% (2/200), and 0.0% (0/85) in cattle, sheep, and pigs, respectively. Toxoplasma gondii seropositivity of 37.90% (106/280), 1.50% (3/200), and 7.10% (6/85) was observed in cattle, sheep, and pigs, respectively. Coxiella burnetii seropositivity of 26.40% (74/280), 15.00% (30/200), and 2.40% (2/85) was observed in cattle, sheep, and pigs, respectively. Coexposure was detected in cattle for positivity against C. burnetii and T. gondii 40.54%, Brucella spp. and T. gondii 1.35%, and Brucella spp. and C. burnetii 4.05%. Coexposure for Brucella spp., C. burnetii, and T. gondii 4.05% was detected in cattle. Coexposure of Brucella spp. and C. burnetii 6.67% was detected in sheep. The AMOS-PCR identified B. abortus in cattle and a mixed infection of B. abortus and B. melitensis in sheep in 64.71% seropositive samples. To our knowledge, the coexposure of Brucella spp., T. gondii, and C. burnetii in cattle has not been reported. Coexposure of Brucella spp. and C. burnetii in cattle and sheep is significant as it results in reproductive losses and constitutes an infectious risk to humans. The detection of antibodies against multiple zoonotic infections in livestock from abattoirs has implications for public health.
Figure S7 from Neurotransmitter Receptor HTR2B Regulates Lipid Metabolism to Inhibit Ferroptosis in Gastric Cancer
Authors: Tu Ru-Hong , Wu Sheng-Ze , Huang Ze-Ning , Zhong Qing , Ye Yin-Hua , Zheng Chao-Hui , Xie Jian-Wei , Wang Jia-Bin , Lin Jian-Xian , Chen Qi-Yue , Huang Chang-Ming , Lin Mi , Lu Jun , Cao Long-Long , Li Ping
Published: December 2023

Supplementary Figure 7. Nuclear translocation of HIF1α upon 5-HT stimulation. (A) Volcano plots of significant DEGs show downregulation of SIRT6 and EGLN2, genes known to negatively regulate HIF1α transcription. These are based on the DEG profiles of HGC-27 cells treated with vehicle versus those treated with 5-HT at 10 μM (n = 3). (B) The proteins Fyn, HIF1α, ABCD1, ACSL4, GPX4, phosphorylated and total Akt, and mTOR were measured by immunoblot in both sh-vector and sh-HTR2B cells. (C and D) Immunofluorescence staining was performed to analyze the subcellular localization of HIF1α in HGC-27 (C) and AGS (D) cells, with or without 5-HT (10 μM) treatment for 24 h. (E-H) AGS and HGC-27 cells from both si-control and si-ABCD1 groups were treated with vehicle or 5-HT (10 μM) for 48 h. Representative confocal images show fluorescence staining in AGS (E) and HGC-27 cells (G) via DCFH-DA dye. Rates of intracellular ROS were measured by DCFH-DA fluorescence in AGS (F) and HGC-27 cells (H) at the indicated time points (n = 3). *p < 0.05, ***p < 0.001; ns, not significant.
Figure S2 from Neurotransmitter Receptor HTR2B Regulates Lipid Metabolism to Inhibit Ferroptosis in Gastric Cancer
Authors: Tu Ru-Hong , Wu Sheng-Ze , Huang Ze-Ning , Zhong Qing , Ye Yin-Hua , Zheng Chao-Hui , Xie Jian-Wei , Wang Jia-Bin , Lin Jian-Xian , Chen Qi-Yue , Huang Chang-Ming , Lin Mi , Lu Jun , Cao Long-Long , Li Ping
Published: December 2023

Supplementary Figure 2. HTR2B plays a protective role in gastric cells. (A and B) Cell viability of HGC-27 (A) and AGS (B) cells at different concentrations of 5-HT in the absence of serum for 24 h (n = 3). (C-H) Cell viability was measured in five gastric cell lines (AGS, HGC-27, BGC-823, MKN-45, and NCI-N87) and the non-malignant cell line (GES-1) in the presence of vehicle or 5-HT (10 μM) (n = 3). *p < 0.05, ** p < 0.01. (I) Cell viability of HGC-27 cells at different concentrations of α-Me-HTP (a specific agonist of HTR2B) and SB204741 (a selective HTR2B antagonist) in the absence of serum for 24 h (n = 3). *p < 0.05, **** p < 0.0001. (J) Representative confocal images showing fluorescence staining in AGS cells treated with vehicle, 5-HT (10 μM), α-Me-HTP (100 μM), or SB204741 (100 μM) for 48 h using the EdU-488 dye. (K) The efficiency of HTR2B knockdown by shRNA interference in AGS and HGC-27 cells was quantified using western blot analysis. (L) Viability of cells exposed to 10 μM 5-HT under standard culture conditions (10% (v/v) FBS) was assessed (n = 3). (M) Cell viability was evaluated in the presence of 100 μM SB204741 under standard culture conditions (10% (v/v) FBS) (n = 3).
Supplementary Figure S2 from Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor–Positive Primary Human Breast Tumors
Authors: Kim Hyunsoo , Whitman Austin A. , Wisniewska Kamila , Kakati Rasha T. , Garcia-Recio Susana , Calhoun Benjamin C. , Franco Hector L. , Perou Charles M. , Spanheimer Philip M.
Published: December 2023

Cell type-specific tamoxifen regulated genes in normal human breast tissue.
Supplementary Figure 3 from Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up
Authors: Lindskrog Sia V. , Birkenkamp-Demtröder Karin , Nordentoft Iver , Laliotis George , Lamy Philippe , Christensen Emil , Renner Derrick , Andreasen Tine G. , Lange Naja , Sharma Shruti , ElNaggar Adam C. , Liu Minetta C. , Sethi Himanshu , Aleshin Alexey , Agerbæk Mads , Jensen Jørgen B. , Dyrskjøt Lars
Published: December 2023

Quality metrics of plasma samples
Supplementary Figure S8 from Differential Benefit of Metronomic Chemotherapy Among Triple-Negative Breast Cancer Subtypes Treated in the IBCSG Trial 22–00
Authors: Joaquin Garcia Andrea , Rediti Mattia , Venet David , Majjaj Samira , Kammler Roswitha , Munzone Elisabetta , Gianni Lorenzo , Thürlimann Beat , Laáng István , Colleoni Marco , Loi Sherene , Viale Giuseppe , Regan Meredith M. , Buisseret Laurence , Rothé Françoise , Sotiriou Christos
Published: December 2023

Cox proportional-hazard analysis for the low-dose CM treatment effect on OS, DRFI and BCFI measures according to the TIME molecular subtypes.
Supplementary Figure S2 from Differential Benefit of Metronomic Chemotherapy Among Triple-Negative Breast Cancer Subtypes Treated in the IBCSG Trial 22–00
Authors: Joaquin Garcia Andrea , Rediti Mattia , Venet David , Majjaj Samira , Kammler Roswitha , Munzone Elisabetta , Gianni Lorenzo , Thürlimann Beat , Laáng István , Colleoni Marco , Loi Sherene , Viale Giuseppe , Regan Meredith M. , Buisseret Laurence , Rothé Françoise , Sotiriou Christos
Published: December 2023

Kaplan-Meier estimates for OS, DFS, DRFI and BCFI measures according to CM maintenance.
Supplementary Table 2 from Impact of Frontline Ivosidenib on Volumetric Growth Patterns in Isocitrate Dehydrogenase–mutant Astrocytic and Oligodendroglial Tumors
Authors: Kamson David Olayinka , Puri Sushant , Sang Yingying , Shi Meihui Jessica , Blair Lindsay , Blakeley Jaishri O. , Laterra John
Published: December 2023

Supplementary Table 2 - Raw data for growth modeling.
Supplementary Table S1 from Upregulation of Indoleamine 2,3-Dioxygenase 1 in Tumor Cells and Tertiary Lymphoid Structures is a Hallmark of Inflamed Non–Small Cell Lung Cancer
Authors: Bessede Alban , Peyraud Florent , Le Moulec Sylvestre , Cousin Sophie , Cabart Mathilde , Chomy François , Rey Christophe , Lara Oren , Odin Ophélie , Nafia Imane , Guegan Jean-Philippe , Italiano Antoine
Published: December 2023

Multivariate analysis of predictive factors associated with progression-free survival (PFS) and overall survival (OS) in patients treated with atezolizumab (n=405).
Supplementary Figure S4 from Upregulation of Indoleamine 2,3-Dioxygenase 1 in Tumor Cells and Tertiary Lymphoid Structures is a Hallmark of Inflamed Non–Small Cell Lung Cancer
Authors: Bessede Alban , Peyraud Florent , Le Moulec Sylvestre , Cousin Sophie , Cabart Mathilde , Chomy François , Rey Christophe , Lara Oren , Odin Ophélie , Nafia Imane , Guegan Jean-Philippe , Italiano Antoine
Published: December 2023

IDO1 tumor expression is increased in infiltrated immune phenotype.
Figure 3 from Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)
Authors: Ring Alistair , Kilburn Lucy S. , Pearson Alex , Moretti Laura , Afshari-Mehr Angelica , Wardley Andrew M. , Gurel Bora , Macpherson Iain R. , Riisnaes Ruth , Baird Richard D. , Martin Sue , Roylance Rebecca , Johnson Hannah , Ferreira Ana , Winter Matthew C. , Dunne Kathryn , Copson Ellen , Hickish Tamas , Burcombe Russell , Randle Kat , Serra Violeta , Llop-Guevara Alba , Bliss Judith M. , Turner Nicolas C.
Published: December 2023

Activity according to biomarker subgroups: confirmed response rate.
Supp Table 3 from ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V.
Published: December 2023

Supp Table 3. ATM co-mutation enrichment analysis in KRAS mutant tumors, in meta-analysis and within individual cohorts.
Supp Table 2 from ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V.
Published: December 2023

Supp Table 2. ATM co-mutation enrichment analysis, in meta-analysis and within individual cohorts.
Figure S5 from A Prospective Study Exploring the Safety and Efficacy of Lenvatinib for Patients with Advanced Hepatocellular Carcinoma and High Tumor Burden: The LAUNCH Study
Authors: Kobayashi Kazufumi , Ogasawara Sadahisa , Maruta Susumu , Okubo Tomomi , Itokawa Norio , Haga Yuki , Seko Yuya , Moriguchi Michihisa , Watanabe Shunji , Shiko Yuki , Takatsuka Hirokazu , Kanzaki Hiroaki , Koroki Keisuke , Inoue Masanori , Nakamura Masato , Kiyono Soichiro , Kanogawa Naoya , Kondo Takayuki , Suzuki Eiichiro , Ooka Yoshihiko , Nakamoto Shingo , Inaba Yosuke , Ikeda Masafumi , Okabe Shinichiro , Morimoto Naoki , Itoh Yoshito , Nakamura Kazuyoshi , Ito Kenji , Azemoto Ryosaku , Atsukawa Masanori , Itobayashi Ei , Kato Naoya
Published: December 2023

Relationship between plasma concentration levels and lenvatinib dose modification
Figure S4 from A Prospective Study Exploring the Safety and Efficacy of Lenvatinib for Patients with Advanced Hepatocellular Carcinoma and High Tumor Burden: The LAUNCH Study
Authors: Kobayashi Kazufumi , Ogasawara Sadahisa , Maruta Susumu , Okubo Tomomi , Itokawa Norio , Haga Yuki , Seko Yuya , Moriguchi Michihisa , Watanabe Shunji , Shiko Yuki , Takatsuka Hirokazu , Kanzaki Hiroaki , Koroki Keisuke , Inoue Masanori , Nakamura Masato , Kiyono Soichiro , Kanogawa Naoya , Kondo Takayuki , Suzuki Eiichiro , Ooka Yoshihiko , Nakamoto Shingo , Inaba Yosuke , Ikeda Masafumi , Okabe Shinichiro , Morimoto Naoki , Itoh Yoshito , Nakamura Kazuyoshi , Ito Kenji , Azemoto Ryosaku , Atsukawa Masanori , Itobayashi Ei , Kato Naoya
Published: December 2023

Transition of RDI of lenvatinib during treatment
Data from Clinico-Genomic Profiling of Conventional and Dedifferentiated Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse Outcomes
Authors: Denu Ryan A. , Yang Richard K. , Lazar Alexander J. , Patel Shalin S. , Lewis Valerae O. , Roszik Jason , Livingston J. Andrew , Wang Wei-Lien , Shaw Kenna R. , Ratan Ravin , Zarzour Maria A. , Bird Justin , Raza Shaan , Akdemir Kadir C. , Rodon Ahnert Jordi , Subbiah Vivek , Patel Shreyaskumar , Conley Anthony P.
Published: December 2023

AbstractPurpose:
Chondrosarcomas are the most common primary bone tumor in adults. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild-type (WT) chondrosarcomas as well as alterations in other genes.
Experimental Design:
We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas.
Results:
IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising in the extremities, associated with higher age at diagnosis, and more common in dedifferentiated chondrosarcomas compared with grades 1–3 conventional chondrosarcoma. There was no difference in survival based on IDH mutation in univariate and multivariate analyses. TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses. TP53 mutation was also associated with higher risk of recurrence following curative-intent surgery and worse survival among patients that presented with de novo metastatic disease.
Conclusions:
IDH mutations are prevalent in chondrosarcoma though were not associated with survival outcomes in this cohort. TP53 mutations were the next most common alteration and were associated with worse outcomes.
Data from Clinical Behavior and Molecular Landscape of Stage I p53-Abnormal Low-Grade Endometrioid Endometrial Carcinomas
Authors: Jamieson Amy , Vermij Lisa , Kramer Claire J.H. , Jobsen Jan J. , Jürgemlienk-Schulz Ina , Lutgens Ludy , Mens Jan Willem , Haverkort Marie A.D. , Slot Annerie , Nout Remi A. , Oosting Jan , Carlson Joseph , Howitt Brooke E. , Ip Philip P.C. , Lax Sigurd F. , McCluggage W. Glenn , Singh Naveena , McAlpine Jessica N. , Creutzberg Carien L. , Horeweg Nanda , Gilks C. Blake , Bosse Tjalling
Published: December 2023

AbstractPurpose:
The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathologic and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort.
Experimental Design:
Previously diagnosed stage I p53abn EC (POLE–wild-type, mismatch repair–proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53 status. IHC profiling, next-generation sequencing, and shallow whole-genome sequencing was performed. Kaplan–Meier method was used for survival analysis.
Results:
We identified 55 stage I p53abn low-grade EEC among 3,387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The IHC and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy-number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients.
Conclusions:
A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence.
Supplementary Table S5 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Mean Tumor volumes and mouse body weights from cell line xenograft studies treated with CLDN18.2-207-ADC (Figure 5B)
Supplementary Table S2 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Binding affinities of CLDN18.2 mAbs and ADC by KinExA
Supplemental Figure S3 from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Induction of apoptosis in CLDN18.2+ human cancer cell lines.
Supplementary Fig S3 from Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers
Authors: Khan Husain Yar , Nagasaka Misako , Aboukameel Amro , Alkhalili Osama , Uddin Md. Hafiz , Bannoura Sahar F. , Mzannar Yousef , Azar Ibrahim , Beal Eliza W. , Tobon Miguel E. , Kim Steve H. , Beydoun Rafic , Baloglu Erkan , Senapedis William , El-Rayes Bassel F. , Philip Philip A. , Mohammad Ramzi M. , Shields Anthony F. , Al Hallak Mohammed Najeeb , Azmi Asfar S.
Published: December 2023

Suppl Fig S3 shows synergistic inhibition of NCI-H2122 cell proliferation by combinations of KPT9274 and KRAS G12C inhibitors
Supplementary Data from FF-10850, a Novel Liposomal Topotecan Achieves Superior Antitumor Activity via Macrophage- and Ammonia-Mediated Payload Release in the Tumor Microenvironment
Authors: Shimoyama Susumu , Okada Ken , Kimura Toshifumi , Morohashi Yasushi , Nakayama Shinji , Kemmochi Sayaka , Makita-Suzuki Keiko , Matulonis Ursula A. , Mori Mikinaga
Published: December 2023

Supplementary Materials and Methods, Figures and Tables
Supplementary Figure 2 from Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition
Authors: Noonepalle Satish Kumar R. , Grindrod Scott , Aghdam Nima , Li Xintang , Gracia-Hernandez Maria , Zevallos-Delgado Christian , Jung Mira , Villagra Alejandro , Dritschilo Anatoly
Published: December 2023

Supplementary Figure 2
Table S4 from Novel Thienoduocarmycin–Trastuzumab ADC Demonstrates Strong Antitumor Efficacy with Favorable Safety Profile in Preclinical Studies
Authors: Valsasina Barbara , Orsini Paolo , Caruso Michele , Albanese Clara , Ciavolella Antonella , Cucchi Ulisse , Fraietta Ivan , Melillo Nicola , Fiorentini Francesco , Rizzi Simona , Salsa Matteo , Isacchi Antonella , Gasparri Fabio
Published: December 2023

Stability of NMS-P528 in mouse, rat, monkey and human plasma
Table S3 from Novel Thienoduocarmycin–Trastuzumab ADC Demonstrates Strong Antitumor Efficacy with Favorable Safety Profile in Preclinical Studies
Authors: Valsasina Barbara , Orsini Paolo , Caruso Michele , Albanese Clara , Ciavolella Antonella , Cucchi Ulisse , Fraietta Ivan , Melillo Nicola , Fiorentini Francesco , Rizzi Simona , Salsa Matteo , Isacchi Antonella , Gasparri Fabio
Published: December 2023

Antiproliferative activity of NMS-P528, MMAE, DXd and doxorubicin in parental and MDR expressing cell lines
Table S2 from Novel Thienoduocarmycin–Trastuzumab ADC Demonstrates Strong Antitumor Efficacy with Favorable Safety Profile in Preclinical Studies
Authors: Valsasina Barbara , Orsini Paolo , Caruso Michele , Albanese Clara , Ciavolella Antonella , Cucchi Ulisse , Fraietta Ivan , Melillo Nicola , Fiorentini Francesco , Rizzi Simona , Salsa Matteo , Isacchi Antonella , Gasparri Fabio
Published: December 2023

Payload antiproliferative activity
Supplementary Figure S3 from C-X-C Motif Chemokine Ligand 9 Correlates with Favorable Prognosis in Triple-Negative Breast Cancer by Promoting Immune Cell Infiltration
Authors: Cao Xi , Song Yu , Wu Huanwen , Ren Xinyu , Sun Qiang , Liang Zhiyong
Published: December 2023

Supplementary Figure S3 shows the expression difference of immune checkpoints (A) and CXCL family members (B) between low- and high-CXCL9 mRNA groups in the basal-like subtype of TCGA BRCA cohort (n=138).
Supplementary Table S1 from Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas
Authors: Ehteda Anahid , Khan Aaminah , Rajakumar Gayathiri , Vanniasinghe Anne S. , Gopalakrishnan Anjana , Liu Jie , Tsoli Maria , Ziegler David S.
Published: December 2023

Multiple comparisons test for Ki67, H2AX, H3K27Ac and H3K27Me3 immunohistochemistry from HSJD-DIPG007 orthotopic animal model
Data from Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: December 2023

Abstract
Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with it's absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic mAb and antibody–drug conjugate (ADC) targeting CLDN18.2. A humanized CLDN18.2 specific mAb, CLDN18.2-307-mAb, was generated through immunization in mice followed by full humanization of the mouse mAb sequences. Antibody clones were screened by flow cytometry for selective binding to membrane bound CLDN18.2. A CLDN18.2-directed ADC (CLDN18.2–307-ADC) was also generated by conjugating MMAE to CLDN18.2 mAb using a cleavable linker. Tissue expression of CLDN18.2 was determined by IHC assay using a CLDN18.2-specific mAb. CLDN18.2-307-mAb binds with high affinity to CLDN18.2-positive (CLDN18.2+) cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). Treatment with this CLDN18.2-mAb blocked the growth of CLDN18.2+ gastric and pancreas cancer cell line xenograft (CDX) models. Upon binding to the extracellular domain of this target, the CLDN18.2-ADC/CLDN18.2 protein was internalized and subsequently localized to the lysosomal compartment inducing complete and sustained tumor regressions in CLDN18.2+ CDXs and patient-derived pancreatic cancer xenografts (PDX). A screen of human cancer tissues, by IHC, found 58% of gastric, 60% of gastroesophageal junction, and 20% of pancreatic adenocarcinomas to be positive for membrane expression of CLDN18.2. These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase I clinical studies.
Data from FF-10850, a Novel Liposomal Topotecan Achieves Superior Antitumor Activity via Macrophage- and Ammonia-Mediated Payload Release in the Tumor Microenvironment
Authors: Shimoyama Susumu , Okada Ken , Kimura Toshifumi , Morohashi Yasushi , Nakayama Shinji , Kemmochi Sayaka , Makita-Suzuki Keiko , Matulonis Ursula A. , Mori Mikinaga
Published: December 2023

Abstract
Topotecan, an approved treatment for refractory or recurrent ovarian cancer, has clinical limitations such as rapid clearance and hematologic toxicity. To overcome these limitations and maximize clinical benefit, we designed FF-10850, a dihydrosphingomyelin-based liposomal topotecan. FF-10850 demonstrated superior antitumor activity to topotecan in ovarian cancer cell line-based xenograft models, as well as in a clinically relevant DF181 platinum-refractory ovarian cancer patient-derived xenograft model. The safety profile was also improved with mitigation of hematologic toxicity. The improved antitumor activity and safety profile are achieved via its preferential accumulation and payload release triggered in the tumor microenvironment. Our data indicate that tumor-associated macrophages internalize FF-10850, resulting in complete payload release. The release mechanism also appears to be mediated by high ammonia concentration resulting from glutaminolysis, which is activated by tumor metabolic reprogramming. In ammonia-rich conditions, FF-10850 released payload more rapidly and to a greater extent than liposomal doxorubicin, a currently approved treatment for ovarian cancer. FF-10850 significantly enhanced antitumor activity in combination with carboplatin or PARP inhibitor without detrimental effects on body weight in murine xenograft models, and demonstrated synergistic antitumor activity combined with anti–PD-1 antibody with the development of tumor antigen-specific immunity. These results support phase I investigation of FF-10850 for the treatment of solid tumors including ovarian cancer (NCT04047251), and further evaluation in combination settings.
Data from Novel Thienoduocarmycin–Trastuzumab ADC Demonstrates Strong Antitumor Efficacy with Favorable Safety Profile in Preclinical Studies
Authors: Valsasina Barbara , Orsini Paolo , Caruso Michele , Albanese Clara , Ciavolella Antonella , Cucchi Ulisse , Fraietta Ivan , Melillo Nicola , Fiorentini Francesco , Rizzi Simona , Salsa Matteo , Isacchi Antonella , Gasparri Fabio
Published: December 2023

Abstract
New antibodies–drug conjugate (ADC) payloads overcoming chemoresistance and killing also poorly proliferating tumors at well-tolerated doses are much desired. Duocarmycins are a well-known class of highly potent cytotoxic agents, with DNA minor groove-binding and alkylation properties, active also in chemoresistant tumors. Although different duocarmycin derivatives have been used during the years as payloads for ADC production, unfavorable physicochemical properties impaired the production of ADCs with optimal features. Optimization of the toxin to balance reactivity and stability features and best linker selection allowed us to develop the novel duocarmycin-like payload–linker NMS-P945 suitable for conjugation to mAbs with reproducible drug–antibody ratio (DAR) >3.5. When conjugated to trastuzumab, it generated an ADC with good internalization properties, ability to induce bystander effect and immunogenic cell death. Moreover, it showed strong target-driven activity in cells and cytotoxic activity superior to trastuzumab deruxtecan tested, in parallel, in cell lines with HER2 expression. High in vivo efficacy with cured mice at well-tolerated doses in HER2-driven models was also observed. A developed pharmacokinetic/pharmacodynamic (PK/PD) model based on efficacy in mice and cynomolgus monkey PK data, predicted tumor regression in patients upon administration of 2 doses of trastuzumab–NMS-P945–ADC at 0.5 mg/kg. Thus, considering the superior physicochemical features for ADC production and preclinical results obtained with the model trastuzumab ADC, including bystander effect, immunogenic cell death and activity in chemoresistant tumors, NMS-P945 represents a highly effective, innovative payload for the creation of novel, next-generation ADCs.
Data from C-X-C Motif Chemokine Ligand 9 Correlates with Favorable Prognosis in Triple-Negative Breast Cancer by Promoting Immune Cell Infiltration
Authors: Cao Xi , Song Yu , Wu Huanwen , Ren Xinyu , Sun Qiang , Liang Zhiyong
Published: December 2023

Abstract
C-X-C motif chemokine ligand 9 (CXCL9) plays an important role in antitumor immunity through the recruitment, proliferation, and activation of immune cells (IC).

Here, we evaluated the expression patterns of CXCL9 and programmed death-ligand 1 (PD-L1) in a cohort of 268 patients with triple-negative breast cancer (TNBC) by tissue microarray (TMA). The correlations between CXCL9 expression in ICs or tumor cells (TC) and clinicopathologic parameters, PD-L1 expression, tumor-infiltrating lymphocytes (TIL) and survival were analyzed in this cohort (n = 268). In addition, we analyzed a TNBC dataset (n = 138) from The Cancer Genome Atlas (TCGA) to identify correlation between CXCL9 expression and other immune gene expression, immune infiltration, and prognosis. The results of the TMA cohort (n = 268) showed that CXCL9 was expressed in 80.6% cases, with elevated expression levels in ICs relative to in TCs (median: 1% vs. 0%). CXCL9 expressed in ≥1% of ICs was categorized as the CXCL9-IC–positive group. CXCL9-IC expression was strongly and positively correlated with the PD-L1 expression, CD3+ TILs, CD4+ TILs, CD8+ TILs, and CD19+ TILs (all P < 0.0001). Survival analyses showed that the CXCL9-IC–positive group demonstrated prolonged disease-free survival (P = 0.038) and overall survival (P = 0.023) compared with the negative group. The analyses from TCGA cohort (n = 138) showed that elevated CXCL9 expression correlated with increased infiltration of B cells, macrophages, natural killer cells, monocytes and increased expression of immune checkpoint molecules and other CXCL family members, including CXCL10 and CXCL11. These findings confirm the regulatory role of CXCL9 in antitumor immunity and suggest a potential role in treatments involving immune checkpoint blockade.
Data from Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas
Authors: Ehteda Anahid , Khan Aaminah , Rajakumar Gayathiri , Vanniasinghe Anne S. , Gopalakrishnan Anjana , Liu Jie , Tsoli Maria , Ziegler David S.
Published: December 2023

Abstract
Diffuse intrinsic pontine gliomas (DIPG) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterized by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRX-E-009–1 is a novel anticancer agent with preclinical activity demonstrated against a range of cancers. We examined the antitumor activity of TRX-E-009–1 against DIPG neurosphere cultures and observed tumor-specific activity with IC50s ranging from 20 to 100 nmol/L, whereas no activity was observed against normal human astrocyte cells. TRX-E-009–1 exerted its anti-proliferative effect through the induction of apoptotic pathways, with marked increases in cleaved caspase 3 and cleaved PARP levels, while also restoring histone H3K27me3 methylation. Co-administration of TRX-E-009–1 and the histone deacetylase (HDAC) inhibitor SAHA extended survival in DIPG orthotopic animal models. This antitumor effect was further enhanced with irradiation. Our findings indicate that TRX-E-009–1, combined with HDAC inhibition, represents a novel, potent therapy for children with DIPG.
Abstract A037: Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer
Authors: Uzunbas Gizem Karsli , McVeigh Quinn , Gupta Akansha , Hoyt Stephanie , Doucette Kristen , Keshishian Hasmik , Carr Steven , Yang Xiaoping , Root David , Cherniack Andrew D , Siegel Franziska , Siegel Stephan , Meyerson Matthew , Greulich Heidi
Published: December 2023

Molecular therapies targeting EGFR-mutant non-small cell lung cancer (NSCLC) have dramatically improved prognosis for patients with the classical activating mutations, L858R and exon 19 deletion. However, tumors harboring EGFR exon 20 insertions have been historically more difficult to target. Agents such as amivantamab and mobocertinib have recently been granted accelerated approval for treatment of lung cancer patients with exon 20 insertions, but agents with an improved selectivity profile versus wild-type EGFR are still needed. BAY 2927088, currently in phase I clinical trials, is a novel reversible inhibitor that targets EGFR exon 20 insertion mutations with decreased activity towards wild-type EGFR. Although most patients with advanced EGFR-mutant NSCLC eventually progress due to acquired resistance to EGFR inhibitors, the mechanisms of resistance to BAY 2927088 are currently unknown. Using two different methods of in vitro resistance generation by inhibitor treatment of sensitive cell lines, we identified mechanisms of intrinsic and acquired resistance to BAY 2927088 and other EGFR inhibitors. Incubation with a high concentration of inhibitor selected for drug-tolerant persister cells that underwent a transcriptional state transition resembling EMT (epithelial-mesenchymal transition). Conversely, gradual escalation of inhibitor concentrations resulted in acquisition of oncogenic NRAS mutations. In a parallel approach, we performed a deep mutational scanning assay of the EGFR D770_N771insSVD kinase domain, replacing each amino acid with every other possible amino acid, identifying both known and novel mutations that cause resistance to BAY 2927088 and other EGFR inhibitors. As expected, the C797S mutation was enriched as a mechanism of acquired resistance only to irreversible EGFR exon 20 insertion inhibitors. Surprisingly, the T790M gatekeeper mutation was found to cause resistance to all EGFR exon 20 insertion inhibitors tested, including irreversible inhibitors. Several novel resistance mutations clustering predominantly in exons 20 and 21 were also identified.

Citation Format: Gizem Karsli Uzunbas, Quinn McVeigh, Akansha Gupta, Stephanie Hoyt, Kristen Doucette, Hasmik Keshishian, Steven Carr, Xiaoping Yang, David Root, Andrew D Cherniack, Franziska Siegel, Stephan Siegel, Matthew Meyerson, Heidi Greulich. Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A037.
Abstract A038: Selective therapeutic antibodies against oncogenic mutations of HER2 ectodomain
Authors: Bang Injin , Hattori Takamitsu , Leloup Nadia , Corrado Alexis , Nyamaa Atekana , Koide Akiko , Geles Ken , Buck Elizabeth , Koide Shohei
Published: December 2023

Dysregulation of HER2 is a well-established mechanism of oncogenesis. Small molecule drugs targeting its kinase domain, and antibody-based drugs such as trastuzumab and pertuzumab targeting its ectodomain have shown efficacy against HER2-overexpression tumors. Separately from HER2 overexpression, oncogenic mutations in the ectodomain in HER2 have been identified in several tumors. As disease drivers that are readily accessible to biologics, these mutants are potentially attractive but still unvalidated therapeutic targets. Current anti-HER2 therapeutic antibodies are indiscriminatory of the mutational state of HER2 and their cross-reactivity to wild-type HER2 can cause toxicity. Here, we have developed antibodies exquisitely selective to HER2 S310F and S310Y, two most common oncogenic mutations in the HER2 ectodomain. These antibodies bound to both HER2 S310F/Y with >100-fold selectivity over the wild-type. Cryo-EM structures of the homodimer of HER2 S310F and an antibody bound to HER2 S310F revealed that these antibodies mimic the dimerization arm of HER2 and inhibit dimerization. The developed antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro. These results establish the feasibility of targeted therapy against S310F/Y-driven cancers and offer promising candidates toward clinical development.

Citation Format: Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide. Selective therapeutic antibodies against oncogenic mutations of HER2 ectodomain [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A038.