bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A044: Meta-analysis of adoptive natural killer cell transfer immunotherapy against solid cancers in human patients
Authors: Jou Eric , Ho Jamie SY
Published: October 2024

Purpose: Recent studies revealed innate lymphoid cells (ILCs) to play critical roles in tumor pathogenesis across multiple preclinical cancer models, however their potential therapeutic efficacy in human cancer patients remain largely unclear. Natural killer (NK) cells, the founding members of group 1 ILCs, exhibit potent anti-tumor cytotoxic activities and NK cell adoptive transfer may serve as a promising immunotherapeutic strategy against solid cancers in patients, however to date this has not been conclusively demonstrated. Methods: A prospectively registered systematic review and meta-analysis (registration ID: CRD42024523774) was conducted assessing the safety and efficacy of NK cell-based adoptive transfer immunotherapies in patients with solid cancers. Major databases including Medline, Embase and Scopus were searched, and all controlled clinical trials utilising NK cell adoptive transfer in patients with solid cancers were included. Results: Of the 4597 articles screened, 44 clinical trials that utilise NK cell-based adoptive transfer therapies in patients with solid cancers were identified, of which 15 were controlled clinical trials and were included in the study. Combined meta-analysis of patients with advanced neuroblastoma, pancreatic, renal, liver, brain, colorectal and lung cancers treated with adoptive NK cell transfer together with standard treatment revealed a 44% and 67% increase in overall clinical response rate (RR=1.44; 95% CI 1.18-1.75, I2=0%, P<0.0001) and complete response rate (RR=1.67, 95% CI 1.02-2.74, I2=0%, P=0.04) respectively, compared to standard treatment alone. Strikingly, the addition of adoptive NK cell transfer immunotherapy reduced the disease progression rate by 53% (RR=0.47, 95% CI 0.34-0.66, I2=0%, P<0.0001), improved progression-free survival by an average of 2.87 months (95% CI=0.58-5.15, I2=0%, P=0.01), and was not associated with increased haematological or systemic adverse effects such as anaemia (P=0.30) and fever (P=0.13). Conclusions: The present study is the first meta-analysis to demonstrate that the addition of adoptive NK cell transfer immunotherapy to existing standard treatment is safe and efficacious in improving clinical response rate and prolonging survival in patients with solid cancers.

Citation Format: Eric Jou, Jamie SY Ho. Meta-analysis of adoptive natural killer cell transfer immunotherapy against solid cancers in human patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A044.
Abstract A054: Recruiting innate immune cells universally: Development of a novel universal innate cell engager for cancer-immunotherapy
Authors: Hutter-Karakoc Idil , Surowka Marlena , Darowski Diana , Klaus Christina , Koller Claudia Ferrara , Hofer Thomas , Freimoser-Grundschober Anne , Mössner Ekkehard , Leclair Stephane , Umana Pablo , Munz Christian , Amann Maria , Klein Christian
Published: October 2024

Novel antibody-engineering approaches have enabled the development of targeted innate cell engagers which redirect innate immune cells to eliminate cancer or suppressive immune cells. These antibodies function through binding to surface antigens on target cells and engaging activating receptors on innate immune cells such as natural killer cells and macrophages. Although early innate cell engagers have shown promise in controlling various cancer types, several major challenges remain in the clinics, including high tumor heterogeneity, low tumor immunogenicity, and reduced efficacy in solid tumors. Here, we present a universal innate cell engager as part of a novel adaptor-based antibody platform. Our universal innate cell engager utilizes a two-step approach combining the power of an adaptor and an effector antibody. First, an Fc-silenced adaptor antibody comprising P329G LALA mutations is used to target the desired antigen in the tumor microenvironment. Then, as an effector antibody, a universal innate cell engager directed against the P329G mutation on the adaptor antibody is used. Innate immune cells are recruited by the universal innate cell engager through its active Fc, leading to antibody-dependent cellular cytotoxicity against the target cells. To maximize innate cell activation, the Fc portion of the universal innate cell engager can be glycoengineered for enhanced FcgRIII affinity.In vitro and in vivo assays showed that our universal innate cell engager is inducing innate immune cell activation and innate immune cell-mediated target cell killing when combined with different antigen-targeted adaptor antibodies. Ultimately, this approach may enable off-the-shelf personalization via combination of universal effector cell engagers and selected adaptor antibodies specific to the patient’s tumor profile.

Citation Format: Idil Hutter-Karakoc, Marlena Surowka, Diana Darowski, Christina Klaus, Claudia Ferrara Koller, Thomas Hofer, Anne Freimoser-Grundschober, Ekkehard Mössner, Stephane Leclair, Pablo Umana, Christian Munz, Maria Amann, Christian Klein. Recruiting innate immune cells universally: Development of a novel universal innate cell engager for cancer-immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A054.
Abstract B017: Chronic stress signaling in disseminated tumor cells promotes immune evasion in breast cancer metastasis
Authors: Cassandras Monica , Huang Yu , Codinachs Ia , Sanchez Xavier , Chuong Jeffrey , Getzler Adam , Flores Pilar Baldominos , Agudo Judith
Published: October 2024

Breast cancer is one of the most lethal diseases for women, with metastasis accounting for over 90% of mortalities. Metastasis occurs when disseminated tumor cells (DTCs) escape detection and killing by surveilling cytotoxic immune cells. The mechanisms of DTC immune evasion are currently not well understood, and this represents a crucial barrier to developing effective therapies to prevent metastatic disease. In the Agudo Lab, we investigate how DTCs evade immune surveillance by utilizing our JEDI CD8+ T cells, which recognize the Green Fluorescent Protein (GFP) to target tumor cells for killing. We used JEDI T cells in combination with a model of breast cancer dissemination in which the cancer cells express GFP. By profiling the GFP+ DTCs that successfully survive JEDI immune attack, we unexpectedly discovered that chronic stress hormone (glucocorticoid) signaling is a top driver of immune evasion in lung DTCs and micro-metastases. Further analysis revealed that activation of the glucocorticoid receptor (GR) promotes an immune evasive state in DTCs that is independent of the suppressive effect of glucocorticoids on immune cells. Indeed, elevated GR activation signatures in patients with primary breast cancer correlates with worse survival. We determined that GR signaling in disseminated breast cancer cells in the lung directly blocks cytotoxic lymphocyte killing by both CD8+ T cells and NK cells, which increases metastatic burden. Mechanistically, DTCs harness stress hormones to repress the death receptor FAS and acquire an overall anti- apoptotic phenotype in order to protect themselves from immune clearance. We determined that pharmacologic antagonism of GR by Mifepristone treatment synergizes with anti-PD1 immunotherapy to reduce metastasis by promoting cytotoxic killing of DTCs and early micro-metastases. Exploiting the mechanisms by which tumor-intrinsic GR signaling prevents immune responses represents promising new avenues for limiting metastasis, and opens the door for new combinatorial treatments with current immunotherapy regimens.

Citation Format: Monica Cassandras, Yu Huang, Ia Codinachs, Xavier Sanchez, Jeffrey Chuong, Adam Getzler, Pilar Baldominos Flores, Judith Agudo. Chronic stress signaling in disseminated tumor cells promotes immune evasion in breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B017.
Abstract B026: Modulation of signalling cross-talk between pJNK and pAKT generates optimal apoptotic response
Authors: Tikader Baishakhi , Biswas Sharmila , Kar Sandip , Viswanathan Ganesh A.
Published: October 2024

Tumor necrosis factor alpha (TNFα) is a well-known modulator of apoptosis by maintaining a balance between proliferation and cell-death in normal cells. Cancer cells often evade apoptotic response following TNFα stimulation by altering signaling cross- talks. Thus, varying the extent of signaling cross-talk could enable optimal TNFα mediated apoptotic dynamics. Herein, we use an experimental data-driven mathematical modeling to quantitate the extent of synergistic signaling cross-talk between the intracellular entities phosphorylated JNK (pJNK) and phosphorylated AKT (pAKT) that orchestrate the phenotypic apoptosis level by modulating the activated Caspase3 dynamics. Our study reveals that this modulation is orchestrated by the distinct dynamic nature of the synergism at early and late phases. We show that this synergism in signal flow is governed by branches originating from either TNFα receptor and NFκB, which facilitates signaling through survival pathways. We demonstrate that the experimentally quantified apoptosis levels semi-quantitatively correlates with the model simulated Caspase3 transients. Interestingly, perturbing pJNK and pAKT transient dynamics fine-tunes this accumulated Caspase3 guided apoptotic response. Thus, our study offers useful insights for identifying potential targeted therapies for optimal apoptotic response.

Citation Format: Baishakhi Tikader, Sharmila Biswas, Sandip Kar, Ganesh A. Viswanathan. Modulation of signalling cross-talk between pJNK and pAKT generates optimal apoptotic response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B026.
Abstract B035: Enhanced tumor infiltration and functionality of anti-GPC3 CAR-T cells in hepatocellular carcinoma through locoregional administration
Authors: Wang Jue , Feng Bo
Published: October 2024

Despite the rapid development of anti-cancer immunotherapy, the prognosis of hepatocellular carcinoma (HCC) patients is far from satisfactory. GPC3 CAR-T cell therapy has shown varied patient response. One of the potential reasons of low response rates is due to the limited CAR-T cell infiltration. Therefore, locoregional GPC3 CAR-T therapy has been a promising option, with a hope of increasing the treatment efficacy. In this study, the therapeutic efficacy and underlying mechanisms of locoregional GPC3 CAR-T cell delivery were explored using orthotopic mouse HCC xenografts. CAR-T cell injection was performed locoregionally (through portal vein) and systemically (through tail vein). Compared to the systemic treatment, locoregional CAR-T therapy could better control the tumour growth, and was associated with improved liver function. In addition, increased percentage of tumour infiltrating CAR-T cells was observed in the locoregional therapy group, with those CAR-T cells gaining increased cytotoxicity, chemotaxis and less exhaustion phenotype. Furthermore, portal vein injection also exhibited a better tumour inhibition ability over tail vein injection on a metastatic model which simultaneously bore both orthotopic and extrahepatic tumour lesions. In the current study, we have demonstrated that locoregional administration of CAR-T cells is associated with increased tumour infiltration and better therapeutic efficacy. Moreover, our results provide insights that locoregional CAR-T therapy could also be employed to the late-stage patients with distant metastasis.

Citation Format: Jue Wang, Bo Feng. Enhanced tumor infiltration and functionality of anti-GPC3 CAR-T cells in hepatocellular carcinoma through locoregional administration [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B035.
Abstract B059: Signaling Requirements for Enhanced CD8+ T Cell Responses in mRNA Cancer Vaccine Immunotherapy
Authors: Rashid Khalid , Lee Hailey R , Creech Amanda L , Luu Tony , Nguyen Katelyn , Teng Pu Lin , Zhao Weihang , Premji Alykhan M , Abt Evan R. , Le Thuc M , Wu Ting-Ting , Pardi Norbert , Radu Caius G
Published: October 2024

The development of nucleoside-modified mRNA vaccines in ionizable lipid-containing nanoparticles (iLNPs) has established a robust cancer immunization platform targeting tumor-associated antigens (TAAs). The substitution of uridine (U) with N1-methylpseudouridine (m1ψ) in these vaccines abrogates innate immune activation, maximizes antigen expression, and enhances the in vivo priming and expansion of adoptively transferred naïve CD8+ T cells. However, antigen-specific T cells primed under immunosilent conditions with m1ψ mRNA-iLNPs exhibit suboptimal effector functions, including impaired cytotoxic cytokine secretion and memory development. Our laboratory has demonstrated that U-mRNA-iLNP vaccines, which elicit a strong type I IFN response, achieve more prolonged tumor growth suppression compared to m1Ψ-mRNA-iLNP vaccines in a preclinical murine model of melanoma. Despite this, the clinical translation of U-mRNA-iLNP vaccines is constrained by dose-limiting toxicities in humans, mediated by cytokines such as IL-1β and IL-6. To overcome this limitation, we explored the co-delivery of a tumor antigen-encoding m1Ψ mRNA-iLNP vaccine and type I IFN in m1ψ mRNA within the context of adoptive cell transfer. Our results demonstrate that prime-boost vaccination with an mRNA-iLNP vaccine, which allows for high antigen expression and a tunable type I IFN response, significantly increases the frequency of antigen-specific CD8+ T cells in circulation and secondary lymphoid organs. Transcriptional profiling of CD8+ T cell subsets expanded by our mRNA vaccine platform revealed a polyfunctional effector signature, including Ifng, Prf1, Gzmb, Tnfα, Klrg1, and Lamp1, as well as enhanced expression of interferon-stimulated genes and costimulatory receptors. We are currently assessing the in vivo efficacy of our mRNA-vaccine platform in melanoma and PDAC orthotopic and liver metastatic models. These studies aim to provide comprehensive mechanistic insights into the requirements of a cancer mRNA-vaccine to generate potent anti-tumor CD8+ T cell responses.

Citation Format: Khalid Rashid, Hailey R Lee, Amanda L Creech, Tony Luu, Katelyn Nguyen, Pu Lin Teng, Weihang Zhao, Alykhan M Premji, Evan R. Abt, Thuc M Le, Ting-Ting Wu, Norbert Pardi, Caius G Radu. Signaling Requirements for Enhanced CD8+ T Cell Responses in mRNA Cancer Vaccine Immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B059.
Therapy-Related Myeloid Neoplasms: Complex Interactions among Cytotoxic Therapies, Genetic Factors, and Aberrant Microenvironment
Authors: Singhal Deepak , Kutyna Monika M. , Hahn Christopher N. , Shah Mithun Vinod , Hiwase Devendra K.
Published: October 2024

Therapy-related myeloid neoplasm (t-MN), characterized by its association with prior exposure to cytotoxic therapy, remains poorly understood and is a major impediment to long-term survival even in the era of novel targeted therapies due to its aggressive nature and treatment resistance. Previously, cytotoxic therapy–induced genomic changes in hematopoietic stem cells were considered sine qua non in pathogenesis; however, recent research demonstrates a complex interaction between acquired and hereditary genetic predispositions, along with a profoundly senescent bone marrow (BM) microenvironment. We review emerging data on t-MN risk factors and explore the intricate interplay among clonal hematopoiesis, genetic predisposition, and the abnormal BM microenvironment.

Significance: t-MN represents a poorly understood blood cancer with extremely poor survival and no effective therapies. We provide a comprehensive review of recent preclinical research highlighting complex interaction among emerging therapies, hereditary and acquired genetic factors, and BM microenvironment. Understanding the risk factors associated with t-MN is crucial for clinicians, molecular pathologists, and cancer biologists to anticipate and potentially reduce its incidence in the future. Moreover, better understanding of the molecular pathogenesis of t-MN may enable preemptive screening and even intervention in high-risk patients.
Supplementary Figure S1 from ATF6 Promotes Colorectal Cancer Growth and Stemness by Regulating the Wnt Pathway
Authors: Rodvold Jeffrey J. , Grimmer Matthew , Ruiz Karen , Marsters Scot A. , Oikonomidi Ioanna , Tan-Aristy Eileen , Pham Victoria C. , Sarkar Tamal , Harnoss Jonathan M. , Shatz-Binder Whitney , Modrusan Zora D. , Wu Thomas D. , Lill Jennie R. , Villemure Elisia , Rudolph Joachim , de Sousa e Melo Felipe , Ashkenazi Avi
Published: October 2024

CRC tumors display elevated expression of ATF6 target genes
Figure 7 from ATF6 Promotes Colorectal Cancer Growth and Stemness by Regulating the Wnt Pathway
Authors: Rodvold Jeffrey J. , Grimmer Matthew , Ruiz Karen , Marsters Scot A. , Oikonomidi Ioanna , Tan-Aristy Eileen , Pham Victoria C. , Sarkar Tamal , Harnoss Jonathan M. , Shatz-Binder Whitney , Modrusan Zora D. , Wu Thomas D. , Lill Jennie R. , Villemure Elisia , Rudolph Joachim , de Sousa e Melo Felipe , Ashkenazi Avi
Published: October 2024

ATF6 inhibition in PDM-272 organoids attenuates cell-cycle progression and promotes multilineage intestinal differentiation. A, UMAPs based on principal components of all single-cell transcriptomes of PDM-272 organoid treated with DMSO (n = 2) or Ceapin-A7 (3 μmol/L; n = 2) for 2 days, as depicted by treatment condition (left) and cluster segmentation (right). B, Pathway enrichment scores of cluster 1 vs. cluster 2 described in A. C, Pathways most significantly downregulated in cluster 2 from cluster 1, as described in A. D, Pathways most significantly upregulated in cluster 2 from cluster 1, as described in A. E, UCell Signature Score of cluster 1 and cluster 2, as described in A. F, Effect of ATF6 inhibition on expression of proteins involved in Wnt signaling. PDM-272 organoid was incubated for 3 days with DMSO (n = 4), inactive Ceapin-A7 (3 μmol/L; n = 3), or ceapin-A7 (3 μmol/L; n = 4) and subjected to global proteome analysis, as described in detail in Materials and Methods. Relative signal intensity calculated based off of abundance of specified protein relative to total protein abundance per sample. G, Effect of ATF6 inhibition on expression of proteins involved in differentiation, as described in F (n ≥ 3). CellCyc, cell cycle; DN, downregulation; UP, upregulation. ****. P < 0.0001.
Figure 5 from ATF6 Promotes Colorectal Cancer Growth and Stemness by Regulating the Wnt Pathway
Authors: Rodvold Jeffrey J. , Grimmer Matthew , Ruiz Karen , Marsters Scot A. , Oikonomidi Ioanna , Tan-Aristy Eileen , Pham Victoria C. , Sarkar Tamal , Harnoss Jonathan M. , Shatz-Binder Whitney , Modrusan Zora D. , Wu Thomas D. , Lill Jennie R. , Villemure Elisia , Rudolph Joachim , de Sousa e Melo Felipe , Ashkenazi Avi
Published: October 2024

β-catenin knockdown phenocopies ATF6 silencing. A, Validation of knockdown in CCK81 cells. CCK81 shATF6 cells and CCK81 shCTNNB1 cells were incubated with Dox (0.5 μg/mL) for 2 and 4 days and analyzed by immunoblotting. Cells treated without Dox (−) were harvested after 4 days. B, CCK81 shATF6 cells and CCK81 shCTNNB1 cells were grown in the absence or presence of Dox for 2 and 4 days and were analyzed by RT-qPCR for Wnt signaling (AXIN2, LGR5, and TCF7), Myc signaling (MYC and CDCA7), and CDKN1A mRNA (n = 3). C, Validation of knockdown in Colo201 cells. Colo201 shATF6.2 cells and Colo201 shCTNNB1 cells were incubated with Dox (0.5 μg/mL) for 3 days and analyzed by immunoblotting. D, Colo201 shATF6.2 cells and Colo201 shCTNNB1 cells were grown in the presence of Dox for 3 days and were analyzed by RT-qPCR for Wnt signaling (AXIN2, LGR5, and TCF7), Myc signaling (MYC and CDCA7), and CDKN1A mRNA (n = 3). E, Viability of CCK81 shATF6 cells and CCK81 shCTNNB1 cells grown in the presence or absence of Dox (0.5 μg/mL) for 5 days (n = 3). F, Viability of Colo201 shATF6.1 cells and Colo201 shCTNNB1 cells grown in the presence or absence of Dox (0.5 μg/mL) for 7 days (n = 6). G, Quantification of cell abundance as determined by relative luminescence units of CCK81 shATF6 cells and CCK81 shCTNNB1 cells that were seeded at specified density and grown with or without Dox (0.5 μg/mL) for 7 days. H, Cell abundance of Colo201 shATF6.1 cells and Colo201 shCTNNB1 cells, as described in G. I, Cell abundance of Colo201 shATF6 cells and Colo201 shCTNNB1 cells grown in ULA plates, as described in G. J, Colo201 and CCK81 shCTNNB1 cells were treated with or without Dox for 3 days and subjected to cell-cycle analysis by EdU incorporation (n = 3). K, Viability of CCK81 shCTNNB1 cells treated separately with Dox (0.5 μg/mL), Ceapin-A7 (10 μmol/L), or concomitantly after 7 days (n = 5). RLU, relative luminescence unit. ** , P < 0.005; ***, P < 0.001; ****, P < 0.0001.
Surviving Twenty Years to Bone and Liver Metastatic Breast Cancer: A Case Reported by Treating Oncologists and the Patient Herself
Authors: Valerio Maria Rosaria , Gebbia Vittorio , Piazza Dario , Campisi Giuseppina , D’Agati Eleonora , Bazzano Monica
Published: October 2024

Introduction: Metastatic breast cancer (MBC) presents an enduring and significant challenge for affected women, requiring sustained commitment over the years. Case Presentation: This paper presents a case of a woman affected by bone and visceral MBC with a very long 20-year survival, excellent quality of life, and high resilience. She is now 51 years old and underwent quadrantectomy for breast cancer in 2005, and in 2013, she developed a recurrence with bone and liver metastases. Despite the widespread stage of the disease with visceral compromise, the patient was treated with a multidisciplinary approach that included surgery, chemotherapy, radiotherapy, hormone therapy, bone target agents, metabolic radiotherapy, and ozone therapy for medication-related osteonecrosis of the jaw. Multidisciplinary management results in a complete clinical and metabolic response to treatment in a visceral metastatic setting. Conclusion: This report supports the possibility of achieving unusual survival outcomes in patients with MBC. This study also highlights the importance of resilience in breast cancer patients who continue to manage their disease and pursue treatment for over 2 decades. Understanding these resilience factors can improve clinical practice and support patients’ long-term care.
Poor Tolerability of Lenvatinib in Elderly Patients with Advanced Hepatocellular Carcinoma after Disease Progression following First-Line Atezolizumab Plus Bevacizumab: A Multicenter Study
Authors: Kato Daisuke , Suzuki Takanori , Matsuura Kentaro , Okayama Kohei , Okumura Fumihiro , Nagura Yoshihito , Sobue Satoshi , Hayashi Katsumi , Kusakabe Atsunori , Hasegawa Izumi , Matoya Sho , Mizoshita Tsutomu , Kimura Yoshihide , Kondo Hiromu , Ozasa Atsushi , Kawamura Hayato , Fujiwara Kei , Nojiri Shunsuke , Kataoka Hiromi ,   Sakurayama Liver Study Group (SLSG)
Published: October 2024

Introduction: We investigated the effectiveness of lenvatinib (LEN) after disease progression following first-line treatment with atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable hepatocellular carcinoma (HCC). Methods: One hundred and ten HCC patients treated with Atez/Bev as first-line systemic chemotherapy were enrolled and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response. We evaluated the treatment efficacy and prognosis after second-line LEN treatment, especially in elderly patients. Results: Of the 110 study patients, 88 patients (80%) were determined to have progressive disease (PD) during the observation periods, and 40 patients received second-line LEN therapy. The 40 patients included 13 patients who were unable to continue LEN until the initial evaluation due to adverse events (AE). The 27 patients who were able to continue LEN therapy (Group A) were significantly younger at initiation of Atez/Bev than those who could not continue (71 vs. 77 years old, p = 0.013). Comparing the OS and PFS between Group A and 44 patients that included 13 patients who were unable to continue LEN and 31 patients did not receive the second-line treatment (Group B), the former had significantly better OS than Group B (31.1 vs. 17.8 months, p = 0.035). Conclusions: The tolerability of second-line LEN therapy was lower in elderly patients, and the OS from the start of Atez/Bev therapy was different depending on the tolerability of second-line LEN therapy.
Phase 2 Trial of Vosoritide Use in Patients with Hypochondroplasia: A Pharmacokinetic/Pharmacodynamic Analysis
Authors: Galetaki Despoina , Zhang Anqing , Qi Yulan , Merchant Nadia , Kanakatti Shankar Roopa , Boucher Kimberly , Shafaei Niusha , Seaforth Raheem , Dham Niti , Dauber Andrew
Published: October 2024

Introduction: Vosoritide is a C-type natriuretic peptide (CNP) analog that binds its receptor on chondrocytes, promoting growth by inhibiting the ERK1/2-MAPK pathway. We previously reported the results of a phase II study in children with hypochondroplasia. Vosoritide led to an average increase in annualized height velocity (AHV) of 1.81 cm/year and gain of 0.36 in height standard deviation (SD) over 12 months. We present here the pharmacokinetic/pharmacodynamic (PK/PD) data from this study and examine the correlations between these parameters and growth outcomes. Methods: We conducted a phase II trial of daily subcutaneous vosoritide (15 μg/kg/day) in 24 prepubertal subjects with hypochondroplasia (12 females, mean age 5.9 ± 2.3 years, mean height −3.29 + 0.68 SD). Plasma vosoritide levels were assayed using an electrochemiluminescence assay. PD markers including serum collagen X biomarker (CXM) and urine cyclic guanosine monophosphate (cGMP) production were measured at day 1, month 6, and month 12 visits. Pearson correlations and regression analyses were performed between PK and PD parameters and growth outcomes. Results: Vosoritide PK parameters were similar to those previously reported in patients with achondroplasia. CXM levels increased from a baseline mean of 22.5 ± 6.5 to 41.6 ± 15.9 ng/mL after 12 months of treatment (p < 0.0001). Urine cGMP increased within 1 h and peaked at 2 h after injection. The mean AUC for cGMP production was not significantly different at each study visit. The maximum change in cGMP AUC correlated with PK AUC (r = 0.46, p = 0.0001). However, drug exposure, as measured by average PK AUC, did not correlate with any growth outcome. CXM levels correlated with the prior 6-month interval height velocity (partial correlation coefficient = 0.40, p = 0.0048). However, change in CXM did not correlate with change in height velocity or change in height SD during treatment. Conclusions: Vosoritide treatment showed improvement in AHV and height SD in children with hypochondroplasia. PK analysis indicates that drug exposure was correlated to global CNP activity as measured by urine cGMP but did not correlate with growth outcomes. More studies are needed to identify specific patient characteristics that can predict response to therapy and clinical outcomes.
Ferroptosis-Mediated Inflammation Promotes Pulmonary Hypertension
Authors: Kazmirczak Felipe , Vogel Neal T. , Prisco Sasha Z. , Patterson Michael T. , Annis Jeffrey , Moon Ryan T. , Hartweck Lynn M. , Mendelson Jenna B. , Kim Minwoo , Calixto Mancipe Natalia , Markowski Todd , Higgins LeeAnn , Guerrero Candace , Kremer Ben , Blake Madelyn L. , Rhodes Christopher J. , Williams Jesse W. , Brittain Evan L. , Prins Kurt W.
Published: October 2024

BACKGROUND:

Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined.

METHODS:

Multiomics and physiological analyses evaluated how ferroptosis inhibition–modulated preclinical PAH. The impact of adeno-associated virus 1–mediated expression of the proferroptotic protein ACSL (acyl-CoA synthetase long-chain family member) 4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension.

RESULTS:

Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-sequencing and proteomics analyses demonstrated ferroptosis was associated with PAH severity. RNA-sequencing, proteomics, and confocal microscopy revealed complement activation and proinflammatory cytokines/chemokines were suppressed by ferrostatin-1. In addition, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-sequencing. Ferroptotic pulmonary arterial endothelial cell damage–associated molecular patterns restructured the transcriptomic signature and mitochondrial morphology, promoted the proliferation of pulmonary artery smooth muscle cells, and created a proinflammatory phenotype in monocytes in vitro. Adeno-associated virus 1-
Acsl4
induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in 6 ferroptosis genes identified a potential link between ferroptosis and pulmonary hypertension severity in the Vanderbilt BioVU repository.

CONCLUSIONS:

Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.
Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease
Authors: Benkhoff Marcel , Barcik Maike , Mourikis Philipp , Dahlmanns Jana , Kahmann Paulina , Wollnitzke Philipp , Hering Moritz , Huckenbeck Tim , Hoppe Julia , Semleit Nina , Deister-Jonas Jennifer , Zako Saif , Seel Jasmin , Coman Cristina , Barth Mareike , Cramer Mareike , Helten Carolin , Wildeis Laura , Hu Hao , Al-Kassis Gabrielle , Metzen Daniel , Hesse Julia , Weber Jessica , Dannenberg Lisa , Akhyari Payam , Lichtenberg Artur , Quast Christine , Gerdes Norbert , Zeus Tobias , Borst Oliver , Kelm Malte , Petzold Tobias , Ahrends Robert , Levkau Bodo , Polzin Amin
Published: October 2024

BACKGROUND:

Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease.

METHODS:

AVD progression and its consequences for cardiac function were examined in a murine wire injury–induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by liquid chromatography-mass spectrometry. Calcification of human valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by liquid chromatography-mass spectrometry.

RESULTS:

Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression.

CONCLUSIONS:

Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.
Hippocampal microscopic fractional anisotropy is reduced in temporal lobe epilepsy
Authors: Arezza Nico J.J. , Abbas Hana H. , Chadwick Caroline , Johnsrude Ingrid S. , Burneo Jorge G. , Suller Marti Ana , Khan Ali R. , Baron Corey A.
Published: October 2024

Surgical resection is the method of choice for treating drug-resistant focal temporal lobe epilepsy (TLE). Postsurgical outcomes are better when magnetic resonance imaging (MRI) findings can localize the seizure focus for resection. However, many patients are MR-negative, meaning the focus cannot be differentiated from normal tissue in relaxation-weighted MRI. Diffusion MRI shows promise as a preoperative marker of neuronal abnormalities due to its sensitivity to cellular changes such as axon damage, indexed by fractional anisotropy. Microscopic fractional anisotropy is a recently introduced diffusion MRI metric that is sensitive to axon integrity regardless of axon orientation in both gray and white matter. In contrast, regular fractional anisotropy is only sensitive to axon integrity in coherently oriented bundles of fibers. This work investigated whether microscopic fractional anisotropy is sensitive to hippocampal abnormalities in drug-resistant TLE. Diffusion MRI was performed on a 3T scanner in 19 patients (age = 31 ± 10 years) with drug-resistant TLE (of which 10 were MR-negative) and 18 healthy volunteers (age = 38 ± 15). A deep-learning method was employed to segment the hippocampus into smaller subregions corresponding to the subiculum, cornu ammonis (CA) 1, CA2/3, and CA4 plus dentate gyrus (DG). Mean measurements of subregion volume, diffusivity, fractional anisotropy, and microscopic fractional anisotropy were compared between cohorts. In a subset of the TLE cohort suspected to have unilateral pathology (n = 15, age = 32 ± 10 years), the percentage differences between measurements ipsilateral and contralateral to the epileptogenic zone were evaluated to assess asymmetry. Microscopic fractional anisotropy was reduced in the hippocampus of drug-resistant TLE patients relative to healthy volunteers. In subregion-specific analysis, microscopic fractional anisotropy was significantly reduced in only the CA4/DG region in patients compared with healthy volunteers, after corrections for multiple comparisons. In the 15 patients with suspected unilateral pathology, microscopic fractional anisotropy was reliably and statistically lower in the ipsilateral CA4/DG region than in the contralateral side. Significant differences were not observed between TLE patients and healthy volunteers, or between hemispheres for patients with suspected unilateral pathology, for the fractional anisotropy or volume metrics. Diffusion MRI may complement standard imaging procedures by detecting abnormalities in MRI-negative patients. Due to its ability to detect abnormality regardless of axon orientation, microscopic fractional anisotropy may improve seizure focus localization in surgical candidates.
Ticanto Miscellany 1. Ticanto xylocarpa (Fabaceae: Caesalpinioideae), a new species from southern China
Authors: JIANG KAI-WEN , YANG HONG , CLARK RUTH P. , CHEN GUO-DI , LIU XIU-TING , LI SHI-JIN , SHI MIAO-MIAO , TU TIE-YAO
Published: October 2024

A new species, Ticanto xylocarpa K. W. Jiang & Shi J. Li is described and illustrated here. It is superficially similar to T. magnifoliolata in its leaf shape and ferruginous young branches and inflorescence axes. However, it is readily distinguished by the ligneous and wingless pods that are dehiscent when mature. Calculations of Area of Occupancy (AOO) and Extent of Occurrence (EOO) suggest that Ticanto xylocarpa meets the criteria for Least Concern (LC) in the IUCN Red List.
Detecting Spatiotemporal Dynamics of Western European Heatwaves Using Deep Learning
Authors: Happé T. , Wijnands J. S. , Fernández-Torres M. Á. , Scussolini P. , Muntjewerf L. , Coumou D.
Published: October 2024

Heatwaves over western Europe are increasing faster than elsewhere, which recent studies have attributed at least partly to changes in atmospheric dynamics. To understand the dynamical drivers of heatwaves, we develop a heatwave classification based on their spatiotemporal evolution over western Europe. We use the KNMI large-ensemble time scale (KNMI-LENTIS) large ensemble dataset of 1600 years of present-day climate and find approximately 14 000 heatwaves. To detect heatwaves, we use the Generalized Density-based Spatial Clustering of Applications with Noise (GDBSCAN) algorithm to cluster together grid points based on their surface temperature extremes. For each heatwave, we extract a 5-day window of daily sea level pressure and streamfunction at 250 hPa, capturing their near-surface and upper-level atmospheric circulation. We use a 3D variational autoencoder (VAE) to extract compact representations from this high-dimensional circulation dataset. We reduce the dimensionality to a 128-dimensional latent space, which we analyze with several algorithms (t-distributed stochastic neighbor embedding, k-means, and the Gaussian mixture model). This yields physically distinct types of heatwaves that are interpretable with known circulation patterns, i.e., U.K. high, Scandinavian high, Atlantic high, and Atlantic low. Our results indicate that the VAE can extract meaningful features from high-dimensional climate data. We find that the heatwave phase space, as found with opt-SNE, is continuous with the four circulation regimes at its corners but with soft boundaries between these circulation regimes, indicating that heatwaves are best categorized in a probabilistic way.

Significance Statement

To better understand the current mismatch in western European extreme temperature trends between observations and climate model simulations, we need to understand the different spatiotemporal atmospheric dynamics that lead to heatwaves in western Europe. We develop a method which identifies physically distinct types of heatwaves over western Europe using deep learning methods. Our method consists of a dimensionality reduction step, using a 3D variational autoencoder, and a clustering step, using k-means and the Gaussian mixture model. We identify four types of heatwaves, as well as transitional heatwaves in between, implying that heatwaves can be best categorized in a probabilistic way. This methodological framework can be applied to classify other extreme events as well.
Dissatisfaction with a Slogan: A Comparative Theology between the Politics of the Church and the Theology of Liberalism
Authors: Pagano Joseph S.
Published: October 2024

This essay offers a comparative theology between the politics of the church and the theology of liberalism. In the fraught conversations about the church and politics in our present-day context, this essay offers a way forward that avoids the pitfalls of anachronistic readings of the New Testament, the coopting of theology by partisan ideologies, the emptying of Christian claims of their distinctive theological idioms, and the desire of the church to be in control. Drawing on recent scholarship on the theology of political liberalism and classical conceptions of the church as polis, this essay brings the politics of the church and the theology of liberalism into a critical comparative dialogue. It offers a helpful way forward for church leaders who seek to be faithful to the politics of the church and engaged in the world in these divisive times.
Legitimizing Digital Technologies in Open Innovation Ecosystems: Overcoming Adoption Barriers in Healthcare
Authors: Randhawa Krithika , Vanhaverbeke Wim , Ritala Paavo
Published: October 2024

Highly regulated industries such as healthcare can reap significant benefits from new digital technologies. However, due to institutional constraints, adopting such technologies is a slow and difficult process. Technology providers need to legitimize their underlying technologies to the customers and other stakeholders in the field. Drawing on multiple case studies in the healthcare industry, this article demonstrates how technology providers deploy two legitimizing practices: solution selling and issue selling. These activities lead to the emergence of open innovation ecosystems that help technology providers overcome adoption barriers.
Examining the Decline in Gender-Specific Youth Offending Since the 1990s: A Decomposition Analysis of Two Cohorts
Authors: Lu Yunmei
Published: October 2024

This study compares gender-specific offending in two cohorts from different historical eras (early 1990s vs. late 2010s). Using KBO decomposition analysis with MTF 12th-grade data ( N = 17,102), the study analyzes changes in social bonds, routine activities, and motivation for crime across genders, assessing their associations with reductions in gender-specific offending. Results suggest consistent behavioral changes across genders. The declines in unstructured socializing and alcohol use are the two most important characteristic changes contributing to the reductions in both male and female offending, but their effect sizes vary across genders. Moreover, the decomposition results underscore that effect changes across cohorts also matter in understanding the gender-specific crime decline, an aspect often overlooked in prior crime trend literature.
How Employees Perceive Planned Organizational Change: Insights from a Workspace Change Project in the German Insurance Industry
Authors: Breutner Natalie , Roth Angela
Published: October 2024

Based on a symbolic–interpretive and social–constructivist research approach, this longitudinal study explores how employees perceive workspace changes. Rich empirical processual data that were continuously collected during the change process were used to analyze workspace changes as a new type of organizational change, thereby contributing to sensemaking research. Three types of change recipients from employees’ responses to a workspace change based on differences in their underlying cognitive, behavioral, and affective patterns throughout the sensemaking process were identified: those with positive attitudes and perceptions, those with negative attitudes and perceptions, and those exhibiting a change toward positive attitudes and perceptions. As a practical contribution, change agents and leaders can gain insights and guidance for managing different employees by considering the individual patterns that trigger changes in employees’ perceptions throughout the change process. These insights about sensemaking also contribute to organizational development and change management research.
Contesting Identities: The Case of Sidis of Gujarat
Authors: Loreng Eva , Haokip Khaikholen
Published: October 2024

The article seeks to explore the contestations about the identity of the Sidis of Gujarat, which is deeply imbricated with experiences of marginalisation and victimisation. Given their African origins, the Sidis are categorised as a diaspora even as they have endeavoured to assert their Schedule Tribe (ST) status in India (a status which so far is segmentally conferred). The association with the diaspora has perpetuated a policy of isolation towards the Sidis and the perception of them as ‘outsiders’. Their aspiration to be identified as ST has been to shift the focus from their diasporic identity and to overcome their historical marginalisation. In this context, the article explores the questions of who the Sidis are, whether are they a diaspora or a tribal community, what ST status means to them, and whether the ST status will aid them in transcending the structural barriers that hinder their integration.
Tribe-Caste Dynamics in South India
Authors: Hebbar Ritambhara , Prakash Soummya
Published: October 2024

There are over 150 tribal communities in South India. Many of them live in remote and forested areas. However, historically, they have had a close relationship with caste society. The dominance of caste is evident in their everyday contexts, economic relations and social status within the local social hierarchy. The article reflects on how the situation of tribes in South India cannot be fully comprehended without acknowledging the overbearing influence of caste ideology and politics on their lives. It will focus on two Scheduled Tribes in South India, the Paniyan and the Koraga, to illustrate practices of untouchability and social deprivation among them. Despite their Scheduled Tribe status, the Paniyan and the Koraga continue to face caste-based discrimination and cannot access basic services provided by the state. There is a deep sense of dispiritedness among them and, increasingly, they are isolating themselves from ‘others’ in their vicinity. Isolation has become an active mode of distancing from caste and asserting their tribal identity. It expresses their rejection of tribal integration, and associated politics, responsible for their marginalisation.
Why are ethno-territorial wars shorter under authoritarian regimes? War-fighting, cost-tolerance and negotiation mechanisms
Authors: Horowitz Shale
Published: October 2024

The civil war (CW) duration literature sometimes finds that authoritarianism leads to shorter wars, and sometimes that regime type has no significant impact. Most commonly, authoritarian regimes (ARs) are expected to fight wars more effectively, thus ending wars earlier by military victory; but also to be more tolerant of war costs, and thus less likely to negotiate ends to wars. We also investigate whether ARs’ willingness to make substantive concessions to rebels – due to their lesser accountability – makes war-ending negotiations more likely. For theoretical and empirical reasons, we limit our universe of cases to the ethno-territorial type of CW and control for the effect of leadership preferences. Our results show that highly ARs tend to have shorter ethno-territorial wars and democracies longer ones; and that the concessions-constraint mechanism is the strongest and the war-costs-tolerance mechanism the weakest.