bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S2 from Clinical and Molecular Features of Long-term Response to Immune Checkpoint Inhibitors in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Thummalapalli Rohit , Ricciuti Biagio , Bandlamudi Chaitanya , Muldoon Daniel , Rizvi Hira , Elkrief Arielle , Luo Jia , Alessi Joao V. , Pecci Federica , Lamberti Giuseppe , Di Federico Alessandro , Hong Lingzhi , Zhang Jianjun , Heymach John V. , Gibbons Don L. , Plodkowski Andrew J. , Ravichandran Vignesh , Donoghue Mark T.A. , Vanderbilt Chad , Ladanyi Marc , Rudin Charles M. , Kris Mark G. , Riely Gregory J. , Chaft Jamie E. , Hellmann Matthew D. , Vokes Natalie I. , Awad Mark M. , Schoenfeld Adam J.
Published: November 2023

Kaplan-Meier curve of progression-free survival (PFS) among patients with long-term response (LTR) in the combined cohort.
Supplementary Table S1 from Phase I Results of Bromodomain and Extra-Terminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies
Authors: Senapati Jayastu , Fiskus Warren C. , Daver Naval , Wilson Nathaniel R. , Ravandi Farhad , Garcia-Manero Guillermo , Kadia Tapan , DiNardo Courtney D. , Jabbour Elias , Burger Jan , Short Nicholas J. , Alvarado Yesid , Jain Nitin , Masarova Lucia , Issa Ghayas C. , Qiao Wei , Khoury Joseph D. , Pierce Sherry , Miller Darla , Sasaki Koji , Konopleva Marina , Bhalla Kapil N. , Borthakur Gautam , Pemmaraju Naveen
Published: November 2023

Study population representation table
Supplementary Figure S10 from SPOP Mutations Target STING1 Signaling in Prostate Cancer and Create Therapeutic Vulnerabilities to PARP Inhibitor–Induced Growth Suppression
Authors: Geng Chuandong , Zhang Man-Chao , Manyam Ganiraju C. , Vykoukal Jody V. , Fahrmann Johannes F. , Peng Shan , Wu Cheng , Park Sanghee , Kondraganti Shakuntala , Wang Daoqi , Robinson Brian D. , Loda Massimo , Barbieri Christopher E. , Yap Timothy A. , Corn Paul G. , Hanash Samir , Broom Bradley M. , Pilié Patrick G. , Thompson Timothy C.
Published: November 2023

Supplementary Fig. S10. Original unedited IB images for representative Western blots experiments (n-2) used in Figure 3E
Tumor Volume Growth Rates and Doubling Times during Active Surveillance of IDH-mutant Low-Grade Glioma
Authors: Bhatia Ankush , Moreno Raquel , Reiner Anne S. , Nandakumar Subhiksha , Walch Henry S. , Thomas Teena M. , Nicklin Philip J. , Choi Ye , Skakodub Anna , Malani Rachna , Prabhakaran Vivek , Tiwari Pallavi , Diaz Maria , Panageas Katherine S. , Mellinghoff Ingo K. , Bale Tejus A. , Young Robert J.
Published: November 2023

Purpose:

Isocitrate dehydrogenase–mutant (IDH-mt) gliomas are incurable primary brain tumors characterized by a slow-growing phase over several years followed by a rapid-growing malignant phase. We hypothesized that tumor volume growth rate (TVGR) on MRI may act as an earlier measure of clinical benefit during the active surveillance period.

Experimental Design:

We integrated three-dimensional volumetric measurements with clinical, radiologic, and molecular data in a retrospective cohort of IDH-mt gliomas that were observed after surgical resection in order to understand tumor growth kinetics and the impact of molecular genetics.

Results:

Using log-linear mixed modeling, the entire cohort (n = 128) had a continuous %TVGR per 6 months of 10.46% [95% confidence interval (CI), 9.11%–11.83%] and a doubling time of 3.5 years (95% CI, 3.10–3.98). High molecular grade IDH-mt gliomas, defined by the presence of homozygous deletion of CDKN2A/B, had %TVGR per 6 months of 19.17% (95% CI, 15.57%–22.89%) which was significantly different from low molecular grade IDH-mt gliomas with a growth rate per 6 months of 9.54% (95% CI, 7.32%–11.80%; P < 0.0001). Using joint modeling to comodel the longitudinal course of TVGR and overall survival, we found each one natural logarithm tumor volume increase resulted in more than a 3-fold increase in risk of death (HR = 3.83; 95% CI, 2.32–6.30; P < 0.0001).

Conclusions:

TVGR may be used as an earlier measure of clinical benefit and correlates well with the WHO 2021 molecular classification of gliomas and survival. Incorporation of TVGR as a surrogate endpoint into future prospective studies of IDH-mt gliomas may accelerate drug development.
Supplementary Table S4 from Targeting Aggressive B-cell Lymphomas through Pharmacological Activation of the Mitochondrial Protease OMA1
Authors: Schwarzer Adrian , Oliveira Matheus , Kleppa Marc-Jens , Slattery Scott D. , Anantha Andy , Cooper Alan , Hannink Mark , Schambach Axel , Dörrie Anneke , Kotlyarov Alexey , Gaestel Matthias , Hembrough Todd , Levine Jedd , Luther Michael , Stocum Michael , Stiles Linsey , Weinstock David M. , Liesa Marc , Kostura Matthew J.
Published: November 2023

Gene level data for Venn Diagram figure of Cell line screening data
Supplementary Table S2 from Targeting Aggressive B-cell Lymphomas through Pharmacological Activation of the Mitochondrial Protease OMA1
Authors: Schwarzer Adrian , Oliveira Matheus , Kleppa Marc-Jens , Slattery Scott D. , Anantha Andy , Cooper Alan , Hannink Mark , Schambach Axel , Dörrie Anneke , Kotlyarov Alexey , Gaestel Matthias , Hembrough Todd , Levine Jedd , Luther Michael , Stocum Michael , Stiles Linsey , Weinstock David M. , Liesa Marc , Kostura Matthew J.
Published: November 2023

Results of screening DLBCL cell lines with compound
Figure S1 from Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid–Antibody–Drug Conjugates
Authors: Nguyen Toan D. , Bordeau Brandon M. , Balthasar Joseph P.
Published: November 2023

Pharmacokinetic model and data
Data from Co-targeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells
Authors: Hardin Haley M. , Dinh Christine T. , Huegel Julianne , Petrilli Alejandra M. , Bracho Olena , Allaf Abdulrahman , Karajannis Matthias A. , Griswold Anthony J. , Ivan Michael E. , Morcos Jacques , Gultekin Sakir H. , Telischi Fred F. , Liu Xue Zhong , Fernandez-Valle Cristina
Published: November 2023

Abstract
Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas. Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective non-surgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell cycle arrest and produced a 44% decrease in tumor growth over a two-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary vestibular schwannoma cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.
Data from Targeting Aggressive B-cell Lymphomas through Pharmacological Activation of the Mitochondrial Protease OMA1
Authors: Schwarzer Adrian , Oliveira Matheus , Kleppa Marc-Jens , Slattery Scott D. , Anantha Andy , Cooper Alan , Hannink Mark , Schambach Axel , Dörrie Anneke , Kotlyarov Alexey , Gaestel Matthias , Hembrough Todd , Levine Jedd , Luther Michael , Stocum Michael , Stiles Linsey , Weinstock David M. , Liesa Marc , Kostura Matthew J.
Published: November 2023

Abstract
DLBCL are aggressive, rapidly proliferating tumors that critically depend on the ATF4-mediated integrated stress response (ISR) to adapt to stress caused by uncontrolled growth, such as hypoxia, amino acid deprivation, and accumulation of misfolded proteins. Here, we show that ISR hyperactivation is a targetable liability in DLBCL. We describe a novel class of compounds represented by BTM-3528 and BTM-3566, which activate the ISR through the mitochondrial protease OMA1. Treatment of tumor cells with compound leads to OMA1-dependent cleavage of DELE1 and OPA1, mitochondrial fragmentation, activation of the eIF2α-kinase HRI, cell growth arrest, and apoptosis. Activation of OMA1 by BTM-3528 and BTM-3566 is mechanistically distinct from inhibitors of mitochondrial electron transport, as the compounds induce OMA1 activity in the absence of acute changes in respiration. We further identify the mitochondrial protein FAM210B as a negative regulator of BTM-3528 and BTM-3566 activity. Overexpression of FAM210B prevents both OMA1 activation and apoptosis. Notably, FAM210B expression is nearly absent in healthy germinal center B-lymphocytes and in derived B-cell malignancies, revealing a fundamental molecular vulnerability which is targeted by BTM compounds. Both compounds induce rapid apoptosis across diverse DLBCL lines derived from activated B-cell, germinal center B-cell, and MYC-rearranged lymphomas. Once-daily oral dosing of BTM-3566 resulted in complete regression of xenografted human DLBCL SU-DHL-10 cells and complete regression in 6 of 9 DLBCL patient-derived xenografts. BTM-3566 represents a first-of-its kind approach of selectively hyperactivating the mitochondrial ISR for treating DLBCL.
Data from Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid-Antibody-Drug Conjugates
Authors: Nguyen Toan Duc. , Bordeau Brandon M. , Balthasar Joseph P.
Published: November 2023

Abstract
Systemic exposure to released cytotoxic payload contributes to the dose-limiting off-target toxicities of anti-cancer antibody-drug conjugates (ADC). In this work, we present an "inverse targeting" strategy to optimize the therapeutic selectivity of maytansinoid-conjugated ADCs. Several anti-maytansinoid sdAbs were generated via phage-display technology with binding IC50s between 10-60 nM. Co-incubation of DM4 with the anti-maytansinoid sdAbs shifted the IC50 of DM4 up to 250-fold. Tolerability and efficacy of 7E7-DM4 ADC, an anti-CD123 DM4-conjugated ADC, were assessed in healthy and in tumor-bearing mice, with and without co-administration of an anti-DM4 sdAb. Co-administration with anti-DM4 sdAb reduced 7E7-DM4 induced-weight loss, where the mean values of percentage weight loss at nadir for mice receiving ADC+saline and ADC+sdAb were 7.9±3% and 3.8±1.3% (p<0.05). In tumor-bearing mice, co-administration of the anti-maytansinoid sdAb did not negatively affect the efficacy of 7E7-DM4 on tumor growth or survival following dosing of the ADC at 1 mg/kg (p=0.49) or at 10 mg/kg (p = 0.9). Administration of 7E7-DM4 at 100 mg/kg led to dramatic weight loss, with 80% of treated mice succumbing to toxicity prior to the appearance of mortality relating to tumor growth in control mice. However, all mice receiving co-dosing of 100 mg/kg 7E7-DM4 with anti-DM4 sdAb were able to tolerate the treatment, which enabled reduction in tumor volume to undetectable levels and to dramatic improvements in survival. In summary, we have demonstrated the utility and feasibility of the application of anti-payload antibody fragments for inverse targeting to improve the selectivity and efficacy of anti-cancer ADC therapy.
Data from Use of Payload Binding Selectivity Enhancers to Improve Therapeutic Index of Maytansinoid–Antibody–Drug Conjugates
Authors: Nguyen Toan D. , Bordeau Brandon M. , Balthasar Joseph P.
Published: November 2023

Abstract
Systemic exposure to released cytotoxic payload contributes to the dose-limiting off-target toxicities of anticancer antibody–drug conjugates (ADC). In this work, we present an “inverse targeting” strategy to optimize the therapeutic selectivity of maytansinoid-conjugated ADCs. Several anti-maytansinoid sdAbs were generated via phage-display technology with binding IC50 values between 10 and 60 nmol/L. Co-incubation of DM4 with the anti-maytansinoid sdAbs shifted the IC50 value of DM4 up to 250-fold. Tolerability and efficacy of 7E7-DM4 ADC, an anti-CD123 DM4-conjugated ADC, were assessed in healthy and in tumor-bearing mice, with and without co-administration of an anti-DM4 sdAb. Co-administration with anti-DM4 sdAb reduced 7E7-DM4–induced weight loss, where the mean values of percentage weight loss at nadir for mice receiving ADC+saline and ADC+sdAb were 7.9% ± 3% and 3.8% ± 1.3% (P < 0.05). In tumor-bearing mice, co-administration of the anti-maytansinoid sdAb did not negatively affect the efficacy of 7E7-DM4 on tumor growth or survival following dosing of the ADC at 1 mg/kg (P = 0.49) or at 10 mg/kg (P = 0.9). Administration of 7E7-DM4 at 100 mg/kg led to dramatic weight loss, with 80% of treated mice succumbing to toxicity before the appearance of mortality relating to tumor growth in control mice. However, all mice receiving co-dosing of 100 mg/kg 7E7-DM4 with anti-DM4 sdAb were able to tolerate the treatment, which enabled reduction in tumor volume to undetectable levels and to dramatic improvements in survival. In summary, we have demonstrated the utility and feasibility of the application of anti-payload antibody fragments for inverse targeting to improve the selectivity and efficacy of anticancer ADC therapy.
Figure S1 from USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma
Authors: Mallard Halle J. , Wan Shibiao , Nidhi Prakriti , Hanscom-Trofy Yvan D. , Mohapatra Bhopal , Woods Nicholas T. , Lopez-Guerrero Jose Antonio , Llombart-Bosch Antonio , Machado Isidro , Scotlandi Katia , Kreiling Natasha F. , Perry Megan C. , Mirza Sameer , Coulter Donald W. , Band Vimla , Band Hamid , Ghosal Gargi
Published: November 2023

Figure S1 shows EWS::FLI1 and USP1 expression in EWS cell lines.
Table S1 from CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: November 2023

Genes included in the CRISPR screening library
Figure S5 from CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: November 2023

Figure S5 shows BH3 mimetics and MCL1 modifiers in combination with BYL719
Figure S3 from CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer
Authors: Stanland Lyla J. , Ang Hazel X. , Hoj Jacob P. , Chu Yunqiang , Tan Patrick , Wood Kris C. , Luftig Micah A.
Published: November 2023

Figure S3 shows that Dasatinib renders cells hyper-sensitive to BYL719
Supplementary Figures 1-9 from Exon Junction Complex Mediates the Cap-Independent Translation of Circular RNA
Authors: Lin Hui-Hsuan , Chang Chiu-Yuan , Huang Yi-Ren , Shen Che-Hung , Wu Yu-Chen , Chang Kai-Li , Lee Yueh-Chun , Lin Ya-Chi , Ting Wen-Chien , Chien Han-Ju , Zheng Yi-Feng , Lai Chien-Chen , Hsiao Kuei-Yang
Published: November 2023

Figure S1. CircRNA candidates identified from 5 polyribosome profiling studies.
Figure S2. Analysis of common targets for circSDHAF2.
Figure S3. circSDHAF2 associated with actively translating ribosomes.
Figure S4. CircSDHAF2 produces proteins.
Figure S5. Intron 2 does not promote nuclear export.
Figure S6. Spliceosome inhibitor suppressed circCoding reporter activity.
Figure S7. Elevated splicing-mediated cap-independent translation activity in CRC cells.
Figure S8. Knockdown of circSDHAF2 suppresses development of tumorspheres.
Figure S9. Demographic information of CRC patients.
Supplementary Figure 3 from Podoplanin Drives Amoeboid Invasion in Canine and Human Mucosal Melanoma
Authors: Shinada Masahiro , Kato Daiki , Motegi Tomoki , Tsuboi Masaya , Ikeda Namiko , Aoki Susumu , Iguchi Takaaki , Li Toshio , Kodera Yuka , Ota Ryosuke , Hashimoto Yuko , Takahashi Yosuke , Chambers James , Uchida Kazuyuki , Kato Yukinari , Nishimura Ryohei , Nakagawa Takayuki
Published: November 2023

PDPN regulates features of amoeboid invasion via the ROCK-MLC2 signaling.
Supplementary Table 6 from Telomerase Upregulation Induces Progression of Mouse BrafV600E-Driven Thyroid Cancers and Triggers Nontelomeric Effects
Authors: Landa Iñigo , Thornton Caitlin E.M. , Xu Bin , Haase Jacob , Krishnamoorthy Gnana P. , Hao Jingzhu , Knauf Jeffrey A. , Herbert Zachary T. , Martínez Paula , Blasco María A. , Ghossein Ronald , Fagin James A.
Published: November 2023

Full list of KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis “up terms” for the BrafV600E vs. BrafV600E+Tert-123C>T comparison.
Data from Podoplanin Drives Amoeboid Invasion in Canine and Human Mucosal Melanoma
Authors: Shinada Masahiro , Kato Daiki , Motegi Tomoki , Tsuboi Masaya , Ikeda Namiko , Aoki Susumu , Iguchi Takaaki , Li Toshio , Kodera Yuka , Ota Ryosuke , Hashimoto Yuko , Takahashi Yosuke , Chambers James , Uchida Kazuyuki , Kato Yukinari , Nishimura Ryohei , Nakagawa Takayuki
Published: November 2023

Abstract
Mucosal melanoma metastasizes at an early stage of the disease in human and dog. We revealed that overexpression of podoplanin in tumor invasion fronts (IF) was related to poor prognosis of dogs with mucosal melanoma. Moreover, podoplanin expressed in canine mucosal melanoma cells promotes proliferation and aggressive amoeboid invasion by activating Rho-associated kinase (ROCK)-myosin light chain 2 (MLC2) signaling. PDPN-ROCK-MLC2 signaling plays a role in cell-cycle arrest and cellular senescence escape as a mechanism for regulating proliferation. Podoplanin induces amoeboid invasion in the IFs of mouse xenografted tumor tissues, similar to canine mucosal melanoma clinical samples. We further identified that podoplanin expression was related to poor prognosis of human patients with mucosal melanoma, and human mucosal melanoma with podoplanin-high expression enriched gene signatures related to amoeboid invasion, similar to canine mucosal melanoma. Overall, we propose that podoplanin promotes canine and human mucosal melanoma metastasis by inducing aggressive amoeboid invasion and naturally occurring canine mucosal melanoma can be a novel research model for podoplanin expressing human mucosal melanoma.
Implications:
Podoplanin could be a new therapeutic target to restrict the metastatic dissemination of canine and human mucosal melanoma.
Data from USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma
Authors: Mallard Halle J. , Wan Shibiao , Nidhi Prakriti , Hanscom-Trofy Yvan D. , Mohapatra Bhopal , Woods Nicholas T. , Lopez-Guerrero Jose Antonio , Llombart-Bosch Antonio , Machado Isidro , Scotlandi Katia , Kreiling Natasha F. , Perry Megan C. , Mirza Sameer , Coulter Donald W. , Band Vimla , Band Hamid , Ghosal Gargi
Published: November 2023

Abstract
In this study, we identify USP1 as a transcriptional target of EWS::FLI1 and demonstrate the requisite function of USP1 in Ewing sarcoma (EWS) cell survival in response to endogenous replication stress. EWS::FLI1 oncogenic transcription factor drives most EWS, a pediatric bone cancer. EWS cells display elevated levels of R-loops and replication stress. The mechanism by which EWS cells override activation of apoptosis or cellular senescence in response to increased replication stress is not known. We show that USP1 is overexpressed in EWS and EWS::FLI1 regulates USP1 transcript levels. USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. Mechanistically, USP1 regulates Survivin (BIRC5/API4) protein stability and the activation of caspase-9 and caspase-3/7 in response to endogenous replication stress. Notably, USP1 inhibition sensitizes cells to doxorubicin and etoposide treatment. Together, our study demonstrates that USP1 is regulated by EWS::FLI1, the USP1–Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes cells to standard of care chemotherapy.
Implications:
High USP1 and replication stress levels driven by EWS::FLI1 transcription factor in EWS are vulnerabilities that can be exploited to improve existing treatment avenues and overcome drug resistance.
Table 1 from Polymorphisms in Cyclooxygenase, Lipoxygenase, and TP53 Genes Predict Colorectal Polyp Risk Reduction by Aspirin in the seAFOod Polyp Prevention Trial
Authors: Davies John R. , Mell Tracey , Fuller Harriett , Harland Mark , Saleh Rasha N.M. , Race Amanda D. , Rees Colin J. , Brown Louise C. , Loadman Paul M. , Downing Amy , Minihane Anne Marie , Williams Elizabeth A. , Hull Mark A.
Published: November 2023

Clinical characteristics of the study cohort of 542 seAFOod trial participants who had a SNP genotype profile and trial colonoscopy outcome data.
Supplementary Methods S2 from Dynamic Risk Prediction of Treatment Discontinuation Using Patient-Reported Outcomes Data in the Phase III NSABP B-35 Trial
Authors: Calsavara Vinicius F. , Henry Norah L. , Hays Ron D. , Kim Sungjin , Luu Michael , Diniz Márcio A. , Gresham Gillian , Cecchini Reena S. , Yothers Greg , Ganz Patricia A. , Rogatko André , Tighiouart Mourad
Published: November 2023

Supplementary Methods S2 provides a statistical description of the prediction error used to assess the model performance.
Supplementary Table S3 from Transposable Elements Are Co-opted as Oncogenic Regulatory Elements by Lineage-Specific Transcription Factors in Prostate Cancer
Authors: Grillo Giacomo , Keshavarzian Tina , Linder Simon , Arlidge Christopher , Mout Lisanne , Nand Ankita , Teng Mona , Qamra Aditi , Zhou Stanley , Kron Ken J. , Murison Alex , Hawley James R. , Fraser Michael , van der Kwast Theodorus H. , Raj Ganesh V. , He Housheng Hansen , Zwart Wilbert , Lupien Mathieu
Published: November 2023

Pluripotent stem cells enriched transposable element families versus individual tissue states
Supplementary Video 1 from SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment
Authors: Sodir Nicole M. , Pathria Gaurav , Adamkewicz Joanne I. , Kelley Elizabeth H. , Sudhamsu Jawahar , Merchant Mark , Chiarle Roberto , Maddalo Danilo
Published: November 2023

Supplementary Video 1 describes SHP2 domains: the N-SH2 (beige), C-SH2 (light green) and PTP (salmon) domains. Shown in blue is the active site of SHP2
Figure 6 from STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts
Authors: Buckbinder Leonard , St. Jean David J. , Tieu Trang , Ladd Brendon , Hilbert Brendan , Wang Weixue , Alltucker Jacob T. , Manimala Samantha , Kryukov Gregory V. , Brooijmans Natasja , Dowdell Gregory , Jonsson Philip , Huff Michael , Guzman-Perez Angel , Jackson Erica L. , Goncalves Marcus D. , Stuart Darrin D.
Published: November 2023

STX-478 combination therapies in ER+ breast cancer models with fulvestrant and palbociclib. A, T47D xenograft tumors were established in female NOD scid gamma immunodeficient (NSG) mice. When tumors reached approximately 200 mm3, mice were randomized and treated as indicated (p.o., oral administration; q.d., daily; q.w., weekly; s.c., subcutaneous injection). Data represent the percent change in tumor volume of individual tumors on day 20 relative to randomization. B and C, NSG mice bearing T47D tumors were given a single dose of vehicle or compound(s) as indicated. Tumors were harvested 4 hours after STX-478 and 24 hours after fulvestrant for Western blot of pAKT (S473) and S6 (S240/244; B), and IHC of pAKT (S473; C). AKT and S6, and pS6 and pAKT (S473) groups were blotted and analyzed together. All samples for a given protein were run on the same gel. A representative vinculin blot is shown. For clarity, images were cropped to remove other compounds. Representative 20× IHC images are shown with a 200-μm scale bar. D, ST-928 xenograft tumors were established in BALB/c nude mice and randomized to indicated treatment groups when tumors reached ∼210 mm3. BrCa, breast cancer. E, Percent change in body weight for D. F, ST1056 xenograft tumors were established in BALB/c nude mice. Mice were randomized to treatment groups as indicated when tumors reached approximately 260 mm3. Mice were treated for 94 days or until removal from the study due to tumor volume. After 94 days, treatment was ended, and tumors were monitored for regrowth. G, Percent change in body weight for F.
Supplementary Table S4 from MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer
Authors: Engstrom Lars D. , Aranda Ruth , Waters Laura , Moya Krystal , Bowcut Vickie , Vegar Laura , Trinh David , Hebbert Allan , Smith Christopher R. , Kulyk Svitlana , Lawson J. David , He Leo , Hover Laura D. , Fernandez-Banet Julio , Hallin Jill , Vanderpool Darin , Briere David M. , Blaj Alice , Marx Matthew A. , Rodon Jordi , Offin Michael , Arbour Kathryn C. , Johnson Melissa L. , Kwiatkowski David J. , Jänne Pasi A. , Haddox Candace L. , Papadopoulos Kyriakos P. , Henry Jason T. , Leventakos Konstantinos , Christensen James G. , Shazer Ronald , Olson Peter
Published: November 2023

Treatment-related treatment-emergent adverse events by preferred term and maximum grade safety population
Supplementary Figure S7 from BCL2 Inhibition Reveals a Dendritic Cell–Specific Immune Checkpoint That Controls Tumor Immunosurveillance
Authors: Zhao Liwei , Liu Peng , Mao Misha , Zhang Shuai , Bigenwald Camille , Dutertre Charles-Antoine , Lehmann Christian H.K. , Pan Hui , Paulhan Nicolas , Amon Lukas , Buqué Aitziber , Yamazaki Takahiro , Galluzzi Lorenzo , Kloeckner Benoit , Silvin Aymeric , Pan Yuhong , Chen Hui , Tian Ai-Ling , Ly Pierre , Dudziak Diana , Zitvogel Laurence , Kepp Oliver , Kroemer Guido
Published: November 2023

Supplementary Figure S7 shows the activation of human peripheral cDC1 cells by BCL2 inhibitors, as well as the in vivo migration of adoptively transferred cDC1 cells that were either WT, BCL2 inhibitor-treated or Bcl2 knock out.
Supplementary Figure S2 from BCL2 Inhibition Reveals a Dendritic Cell–Specific Immune Checkpoint That Controls Tumor Immunosurveillance
Authors: Zhao Liwei , Liu Peng , Mao Misha , Zhang Shuai , Bigenwald Camille , Dutertre Charles-Antoine , Lehmann Christian H.K. , Pan Hui , Paulhan Nicolas , Amon Lukas , Buqué Aitziber , Yamazaki Takahiro , Galluzzi Lorenzo , Kloeckner Benoit , Silvin Aymeric , Pan Yuhong , Chen Hui , Tian Ai-Ling , Ly Pierre , Dudziak Diana , Zitvogel Laurence , Kepp Oliver , Kroemer Guido
Published: November 2023

Supplementary Figure S2 contains data suggesting the activation of the dsDNA/cGAS/STING/Type IFN pathway by BCL2 inhibition.
Supplementary Figure S10 from BCL2 Inhibition Reveals a Dendritic Cell–Specific Immune Checkpoint That Controls Tumor Immunosurveillance
Authors: Zhao Liwei , Liu Peng , Mao Misha , Zhang Shuai , Bigenwald Camille , Dutertre Charles-Antoine , Lehmann Christian H.K. , Pan Hui , Paulhan Nicolas , Amon Lukas , Buqué Aitziber , Yamazaki Takahiro , Galluzzi Lorenzo , Kloeckner Benoit , Silvin Aymeric , Pan Yuhong , Chen Hui , Tian Ai-Ling , Ly Pierre , Dudziak Diana , Zitvogel Laurence , Kepp Oliver , Kroemer Guido
Published: November 2023

Supplementary Figure S10 shows selective cDC1 depletion by cytochrome c injections, as well as the effects of cDC1 depletion on BCL2 inhibitor-induced T cell activation and fibrosarcoma control.
Data from STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts
Authors: Buckbinder Leonard , St. Jean David J. , Tieu Trang , Ladd Brendon , Hilbert Brendan , Wang Weixue , Alltucker Jacob T. , Manimala Samantha , Kryukov Gregory V. , Brooijmans Natasja , Dowdell Gregory , Jonsson Philip , Huff Michael , Guzman-Perez Angel , Jackson Erica L. , Goncalves Marcus D. , Stuart Darrin D.
Published: November 2023

Abstract
Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Kα is associated with severe hyperglycemia and rash, which limits alpelisib use and suggests that selectively targeting mutant PI3Kα could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Kα inhibitor that selectively targets prevalent PI3Kα helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2− xenograft tumor models.
Significance:
These preclinical data demonstrate that the mutant-selective, allosteric PI3Kα inhibitor STX-478 provides robust efficacy while avoiding the metabolic dysfunction associated with the nonselective inhibitor alpelisib. Our results support the ongoing clinical evaluation of STX-478 in PI3Kα-mutated cancers, which is expected to expand the therapeutic window and mitigate counterregulatory insulin release.

See related commentary by Kearney and Vasan, p. 2313.

This article is featured in Selected Articles from This Issue, p. 2293
Supplementary Figure 4 from slan+ Monocytes Kill Cancer Cells Coated in Therapeutic Antibody by Trogoptosis
Authors: Finotti Giulia , Pietronigro Enrica , Balanzin Camillo , Lonardi Silvia , Constantin Gabriela , Chao Mark P. , Tecchio Cristina , Vermi William , Cassatella Marco A.
Published: November 2023

Assessment of ADCC and trogocytosis exerted by NK cells, as well as of pathways required for ADCC mediated by slan+-monocytes.
Data from Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function
Authors: Zhang Caimei , Kadu Siddhant , Xiao Yansen , Johnson Omar , Kelly Andre , O'Connor Roddy S. , Lai Meizan , Kong Hong , Srivatsa Sriram , Tai Victoria , Greenblatt Eli , Holmes Matthew , Riley James L. , June Carl H. , Sheppard Neil C.
Published: November 2023

Abstract
Natural killer (NK) cells are frequently expanded for the clinic using irradiated, engineered K562 feeder cells expressing a core transgene set of membrane-bound (mb) IL15 and/or mbIL21 together with 41BBL. Prior comparisons of mbIL15 to mbIL21 for NK expansion lack comparisons of key attributes of the resulting NK cells, including their high-dimensional phenotype, polyfunctionality, the breadth and potency of cytotoxicity, cellular metabolism, and activity in xenograft tumor models. Moreover, despite multiple rounds of K562 stimulation, studies of sequential use of mbIL15- and mbIL21-based feeder cells are absent. We addressed these gaps and found that using mbIL15- versus mbIL21-based feeder cells drove distinct phenotypic and functional profiles. Feeder cells expressing mbIL15 alone drove superior functionality by nearly all measures, whereas those expressing mbIL21 alone drove superior yield. In combination, most attributes resembled those imparted by mbIL21, whereas in sequence, NK yield approximated that imparted by the first cytokine, and the phenotype, transcriptome, and function resembled that driven by the second cytokine, highlighting the plasticity of NK cell differentiation. The sequence mbIL21 followed by mbIL15 was advantageous in achieving significant yields of highly functional NK cells that demonstrated equivalent in vivo activity to those expanded by mbIL15 alone in two of three xenograft models. Our findings define the impact of mbIL15 versus mbIL21 during NK expansion and reveal a previously underappreciated tradeoff between NK yield and function for which sequential use of mbIL21-based followed by mbIL15-based feeder cells may be the optimal approach in many settings.
Supplementary Tables S1 to S15 from Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells
Authors: Nelde Annika , Schuster Heiko , Heitmann Jonas S. , Bauer Jens , Maringer Yacine , Zwick Melissa , Volkmer Jens-Peter , Chen James Y. , Stanger Anna M. Paczulla , Lehmann Ariane , Appiah Bismark , Märklin Melanie , Rücker-Braun Elke , Salih Helmut R. , Roerden Malte , Schroeder Sarah M. , Häring Max-Felix , Schlosser Andreas , Schetelig Johannes , Schmitz Marc , Boerries Melanie , Köhler Natalie , Lengerke Claudia , Majeti Ravindra , Weissman Irving L. , Rammensee Hans-Georg , Walz Juliane S.
Published: November 2023

The Supplementary Tables file includes Tables S1 to S15.
Table S1: Frequencies of CD34+CD38- LSCs within primary AML patient samples.
Table S2: Immunopeptidomics cohort overview.
Table S3: Patient characteristics of AML immunopeptidomics cohort.
Table S4: AML- and AML/LSC-associated HLA class I targets.
Table S5: AML/LSC shared HLA class I-presented antigens.
Table S6: AML- and AML/LSC-associated HLA class II peptide, protein, and hotspot targets.
Table S7: AML/LSC shared HLA class II-presented peptide targets.
Table S8: Recurrent AML mutations included in neoepitope screening.
Table S9: Characteristics of AML patient samples used for T cell-based assays.
Table S10: Characteristics of HV samples used for T cell-based assays.
Table S11: Immunopeptidome diversity according to demographics and disease characteristics.
Table S12: Impact of demographics and disease characteristics on patient outcome in the immunopeptidome survival analysis group.
Table S13: Patient characteristics of immunopeptidome survival analysis group.
Table S14: Patient characteristics of immune response survival analysis group.
Table S15: Impact of demographics and hematopoietic stem cell transplantation on patient outcome in the immune response survival group.
Downstaging and Pathological Complete Response of Locally Recurrent Sarcomatoid Renal Cell Carcinoma under Pembrolizumab and Lenvatinib: A Case Report and Review of Literature
Authors: Ell Jascha , Balz Philipp , Manava Panagiota , Hüttenbrink Clemens
Published: November 2023

The advent of immune checkpoint inhibition opened new perspectives for patients with recurrent or metastasized renal cell carcinoma. In case of recurrent disease, surgical resection remains the most promising therapeutic option. Surgical resection is associated with improved overall survival and demonstrated curative potential given complete resection of metastases can be performed. This report presents the case of a patient with local recurrence of dedifferentiated sarcomatoid renal cell carcinoma approximately 1 year after initial open lumbar nephrectomy. After initial evaluation, surgical removal was deemed infeasible and an induction therapy with pembrolizumab and lenvatinib was initiated. After 3 months, corresponding to 5 cycles of pembrolizumab, the tumor showed a partial response on imaging control and was successfully resected en bloc. Histopathological examination of the specimen revealed no evidence of viable neoplastic cells. This is the first report describing a complete pathological response of a locally recurrent dedifferentiated sarcomatoid renal cell carcinoma after treatment with pembrolizumab and lenvatinib. Overall, the combination therapy was well tolerated with a maximum Common Terminology Criteria for Adverse Events Level of Two. These findings underline the potential of multimodal therapeutic strategies for recurrent renal cell carcinoma, such as induction therapies to downstage initially nonresectable masses, and highlight the need for prospective studies to allow for evidence-based treatment plans.
Deficiency of Complement C3a and C5a receptors Does Not Prevent Angiotensin II–Induced Hypertension and Hypertensive End-Organ Damage
Authors: Bode Marlies , Herrnstadt Georg R. , Dreher Leonie , Ehnert Nicolas , Kirkerup Pia , Lindenmeyer Maja T. , Meyer-Schwesinger Catherine F. , Ehmke Heimo , Köhl Jörg , Huber Tobias B. , Krebs Christian F. , Steinmetz Oliver M. , Wiech Thorsten , Wenzel Ulrich O.
Published: November 2023

BACKGROUND:

Complement may drive the pathology of hypertension through effects on innate and adaptive immune responses. Recently an injurious role for the anaphylatoxin receptors C3aR (complement component 3a receptor) and C5aR1 (complement component 5a receptor) in the development of hypertension was shown through downregulation of Foxp3
+
(forkhead box protein 3) regulatory T cells. Here, we deepen our understanding of the therapeutic potential of targeting both receptors in hypertension.

METHODS:

Data from the European Renal cDNA Bank, single cell sequencing and immunohistochemistry were examined in hypertensive patients. The effect of C3aR or C3aR/C5aR1 double deficiency was assessed in two models of Ang II (angiotensin II)-induced hypertension in knockout mice.

RESULTS:

We found increased expression of C3aR, C5aR1 and Foxp3 cells in kidney biopsies of patients with hypertensive nephropathy. Expression of both receptors was mainly found in myeloid cells. No differences in blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation) or cardiac injury (cardiac fibrosis, heart weight, gene expression) between control and mutant mice was discerned in C3aR
-/-
as well as C3aR/C5aR1
-/-
double knockout mice. The number of renal Tregs was not decreased in Ang II as well as in DOCA salt induced hypertension.

CONCLUSIONS:

Hypertensive nephropathy in mice and men is characterized by an increase of renal regulatory T cells and enhanced expression of anaphylatoxin receptors. Our investigations do not corroborate a role for C3aR/C5aR1 axis in Ang II–induced hypertension hence challenging the concept of anaphylatoxin receptor targeting in the treatment of hypertensive disease.
Prunus quanzhouensis: a newly discovered species of Prunus subgen. Cerasus (Rosaceae) from northeastern Guangxi, China
Authors: LIANG SHENG-HUA , QIN BO , HUANG YAO-HENG , TANG LI-MING , ZHANG ZHAN-JIANG , LI CUI , HE YING-HUI , JIANG RI-HONG , LI JIAN-LING
Published: November 2023

Prunus quanzhouensis is a new species of Rosaceae discovered in Guangxi, China, which is here described and illustrated. Despite its morphological similarities to P. campanulata, P. conradinae and P. xueluoensis, it can be distinguished from them by being shrubs or small trees, with 1.5–3.0 m tall, leaves with 10–13 pairs of lateral veins, abaxially glabrous involucral bracts, adaxially appressed villous bracts, flowers measuring 1–1.2 cm in diameter, tubular hypanthium with about 9×3 mm, oblique sepals, 30–35 stamens, and a style that is villous and longer than the stamens. Less than six populations of this new species have been found in the type locality, with approximately 130 mature individuals, which accounted for more than 95% of the total population. Based on direct observation in the field and the IUCN Red List Categories and Criteria, P. quanzhouensis is classified as Endangered (EN).
Effects of Workplace Ostracism on Pro-Job Unethical Behavior: The Role of Moral Disengagement, Interpersonal Sensitivity and Self-Serving Political Will
Authors: Liu Xin , Zhang Hantai , Yu Xuan
Published: November 2023

Drawing on social cognition theory, this study aims to investigate the impact of workplace ostracism on pro-job unethical behavior by studying the mediating function of moral disengagement and the moderating function of interpersonal sensitivity and self-serving political will. Data were congregated from 527 Chinese employees. A positive effect of workplace ostracism on pro-job unethical behavior was found, which was partially mediated by moral disengagement. In addition, interpersonal sensitivity strengthened the connection between workplace ostracism and moral disengagement, and self-serving political will strengthened the connection between moral disengagement and pro-job unethical behavior. Both theoretical and practical value are discussed in the study.
5α-Hydroxycostic acid inhibits choroidal neovascularization in rats through a dual signalling pathway mediated by VEGF and angiopoietin 2
Authors: Lei Wulong , Xu Huan , Yao Hao , Li Lanjiao , Wang Menglei , Zhou Xiyuan , Liu Xueqin
Published: November 2023

Background

5α-Hydroxycostic acid is a eudemane sesquiterpene that is isolated from the natural plant, Laggera alata. It exerts anti-inflammatory and anti-angiogenic effects on human breast cancer cells, but its role and underlying mechanism in choroidal neovascularization (CNV) are still unclear. We conducted a study to verify that 5α-Hydroxycostic acid can inhibit the formation and leakage of CNV, and describe the possible dual pathway by which it exerts its inhibitory effects in this process.

Methods

An in vitro model of choroidal neovascularization was established using VEGF164, while a rat model of choroidal neovascularization was established using a 532 nm laser. In both models, the effects of 5α-Hydroxycostic acid in vivo and in vitro were evaluated to determine its inhibitory effect on abnormal cell proliferation, migration and tubule formation, as well as its effect on pathological changes in choroidal tissues and the area of neovascularization leakage in rats. The levels of components in the VEGF/VEGFR and Ang2/Tie2 signaling pathways were measured in tissues and cells.

Results

In vitro experiments have shown that 5α-Hydroxycostic acid can inhibit abnormal cell proliferation, migration and angiogenesis. Additionally, 5α-Hydroxycostic acid enhances cell adhesion by inhibiting the phosphorylation pathways of VEGFR2 and Tie2. In vivo experiments demonstrated that 5α-Hydroxycostic acid has a positive therapeutic effect on choroidal neovascularization in rats. It can effectively reduce vascular leakage, consistent with the results of the cell experiments.

Conclusion

5α-Hydroxycostic acid can inhibit choroidal neovascularization by interfering with the VEGF- and Ang2/Tie2-related pathways, and it may be a good candidate drug for treating CNV.
Concurrent fabry disease and immunoglobulin a nephropathy: a case report
Authors: Zhou Li-Na , Dong Shao-Shao , Zhang Sheng-Ze , Huang Li-Wa , Huang Wen
Published: November 2023

Background

Fabry disease (FD) is an X-linked, hereditary dysfunction of glycosphingolipid storage caused by mutations in the GLA gene encoding alpha-galactosidase A enzyme. In rare cases, FD may coexist with immunoglobulin A nephropathy (IgAN). We describe a case of concurrent FD, IgAN, and dilated cardiomyopathy-causing mutations in the TTN and BAG3 genes, which has not been reported previously.

Case presentation

A 60-year-old female patient was admitted with a one-week history of facial and lower-limb edema, two-year history of left ventricular hypertrophy and sinus bradycardia, and recurring numbness and pain in three lateral digits with bilateral thenar muscle atrophy. Renal biopsy revealed concurrent FD (confirmed via an alpha-galactosidase A enzyme assay, Lyso-GL-3 quantification, and GLA gene sequencing) and IgAN. Heterozygous mutations in the TTN (c.30,484 C > A;p.P10162T) and BAG3 (c.88 A > G;p.I30V) genes were observed. The patient reported that two of her brothers had undergone kidney transplantation; one died suddenly at 60 years of age, and the other required a cardiac pacemaker. The 35-year-old son of the patient was screened for the GLA gene mutation and found to be positive for the same mutation as the patient. The patient was administered oral losartan (50 mg/day). Enzyme replacement therapy was refused due to financial reasons. Her renal and cardiac functions were stable yet worth closely monitoring during follow-up.

Conclusion

The family history of patients with concurrent heart and renal diseases should be assessed in detail. Genetic testing and histological examinations are essential for diagnosing FD with IgAN.
A cross-sectional study of symptoms and health-related quality of life in menopausal-aged women in China
Authors: Rautenberg Tamlyn A. , Ng Shu Kay Angus , Downes Martin
Published: November 2023

Objective

To measure symptoms and health-related quality of life in a cross-sectional cohort of menopausal-aged women in China.

Method

A cross-sectional survey was conducted in a general population cohort of 2,000 Chinese females over the age of 45 years. Patients completed the Chinese version of the EuroQol-5D five level (EQ5D5L) health-related quality of life instrument via Personal Digital Assistant. Raw scores were converted to utility tariffs using value sets for China. Statistical analysis included Pearson’s chi-square test, z test for multiple comparisons with adjustment by the Bonferroni method, independent-sample t-test, ANOVA, and adjustment by the Tukey method for multiple comparison. Results were considered statistically significant when p < 0.05 and the study was reported according to the STROBE recommendations.

Results

In a cohort of 2000 women, 732 (37%) were premenopausal, 798 (40%) were perimenopausal and 470 (23%) were postmenopausal. Perimenopausal women reported significantly more symptoms (91%) compared to premenopausal (77%) and postmenopausal (81%) women. Health-related quality of life was significantly lower in symptomatic perimenopausal women compared to premenopausal (0.919, p < 0.05) and postmenopausal (0.877, p < 0.05) women. Within each group there was a statistically significant difference between the health-related quality of life of women with symptoms compared to without symptoms.

Conclusion

The perimenopausal phase of menopause is associated with significantly more symptoms and significantly lower HRQoL compared to premenopausal and postmenopausal phases.