tbuckley/cabot-search huggingface dataset:
<scp>Real‐Life</scp> experience with hydroxyurea in patients with sickle cell disease: Results from the prospective <scp>ESCORT‐HU</scp> cohort study
Authors: Mariane de Montalembert, Ersi Voskaridou, Lena Oevermann, Giovanna Cannas, Anoosha Habibi, Gylna Loko, Laure Joseph, Raffaella Colombatti, Pablo Bartolucci, Valentine Brousse, Frédéric Galactéros
Journal: American Journal of Hematology (2021)

Several controlled studies have evidenced good efficacy and short-term and mid-term safety profiles for hydroxyurea (HU), which has become the cornerstone for prevention of sickle-cell disease (SCD)-related vaso-occlusive crises. However, there are few large-scale reports on its long-term use and certain caregivers and patients have concerns about its safety. Following the licensing of HU in Europe for children and adults with severe forms of SCD, ESCORT-HU was designed as a Phase IV observational cohort study. It included 1906 participants, of whom 55% were adults. The most common hemoglobin (Hb) genotypes were HbSS (84.7%) and HbSβ+ (7.0%). The median duration of follow-up was 45 months, for a total of 7309 patient-years of observation. The dose of HU after 1 year was 20.6 mg/kg/d for children and 16.3 mg/kg/d for adults. There was a statistically significant decrease in the number of vaso-occlusive episodes lasting >48 h, acute chest syndrome episodes, hospitalizations, and the percentage of patients requiring blood transfusions within the first 12 months relative to the year before enrolment. Neutropenia and thrombocytopenia were the most commonly reported adverse effects. No new HU toxicity was identified. Overall, 125 pregnancies were reported in 101 women and no malformations were observed in the neonates. There were 12 pregnancies for partners of male patients treated with HU. One case of fatal myelodysplastic syndrome was reported, for which a causal association with HU could not be excluded. This cohort study of patients with SCD highlights the positive benefit-to-risk ratio of HU in children and adults.
Evaluation of a procaspase-3 activator with hydroxyurea or temozolomide against high-grade meningioma in cell culture and canine cancer patients
Authors: Emily J Tonogai, Shan Huang, Rachel C Botham, Matthew R Berry, Stephen K Joslyn, Gregory B Daniel, Zixin Chen, Jianghong Rao, Xiang Zhang, Falguni Basuli, John H Rossmeisl, Gregory J Riggins, Amy K LeBlanc, Timothy M Fan, Paul J Hergenrother
Journal: Neuro-Oncology (2021)

Abstract Background High-grade meningioma is an aggressive type of brain cancer that is often recalcitrant to surgery and radiotherapy, leading to poor overall survival. Currently, there are no FDA-approved drugs for meningioma, highlighting the need for new therapeutic options, but development is challenging due to the lack of predictive preclinical models. Methods To leverage the known overexpression of procaspase-3 in meningioma, PAC-1, a blood-brain barrier penetrant procaspase-3 activator, was evaluated for its ability to induce apoptosis in meningioma cells. To enhance the effects of PAC-1, combinations with either hydroxyurea or temozolomide were explored in cell culture. Both combinations were further investigated in small groups of canine meningioma patients and assessed by MRI, and the novel apoptosis tracer, [18F]C-SNAT4, was evaluated in patients treated with PAC-1 + HU. Results In meningioma cell lines in culture, PAC-1 + HU are synergistic while PAC-1 + TMZ show additive-to-synergistic effects. In canine meningioma patients, PAC-1 + HU led to stabilization of disease and no change in apoptosis within the tumor, whereas PAC-1 + TMZ reduced tumor burden in all three canine patients treated. Conclusions Our results suggest PAC-1 + TMZ as a potentially efficacious combination for the treatment of human meningioma, and also demonstrate the utility of including pet dogs with meningioma as a means to assess anticancer strategies for this common brain tumor.
Abstract 2661: Role of NKX2-1 in thyroid neoplasms induced by iodine-deficiency and radiation
Authors: Yo-Taro Shirai, Yoshinori Takizawa, Manabu Iwadate, Jorge Paiz, Shigetoshi Yokoyama, Masaaki Miyakoshi, Jerrold M. Ward, Shioko Kimura
Journal: Cancer Research (2021)

Abstract The multi-step carcinogenesis model, including the adenoma-carcinoma sequence, has been proposed in many cancers including those of colon, pancreas, and thyroid. BRAF activation is among the reported gene mutations important for thyroid carcinogenesis. However, the role of NKX2-1, a master regulator of thyroid development and function, in thyroid carcinogenesis remains elusive. In this study, we investigated the role of NKX2-1 in thyroid neoplasm formation using thyroid-specific Nkx2-1 conditional KO mice, Nkx2-1(fl/fl);TPO-Cre (cKO mice). Nkx2-1(fl/fl) (WT) and cKO mice were each allotted to four groups: 1. Control Diet, 2. Control Diet + Radiation, 3. Low Iodine Diet (LID), 4. LID + Radiation. Whole body gamma-irradiation (2 Gy, 3 times every other day) was carried out at 4-8 weeks of age, followed by switching the diet to either Control Diet or LID. Thyroid histology was examined at 1.1-1.3 years after the start of the diet. In both WT and cKO mice, iodine-deficiency, regardless of radiation, induced diffuse hyperplasia (goiter) in more than 50% of the mice, and increased the incidence of focal hyperplasia considered as a preneoplastic lesion. Adenoma formation was only observed in LID-treated mice regardless of radiation, suggesting that iodine-deficiency, but not radiation, is a key factor for mouse thyroid adenoma formation. The incidence of adenoma formation was significantly higher in cKO mice than WT mice in LID + Radiation group (14% for WT vs 52% for cKO, in progress). In addition, carcinoma formation was observed only in LID + Radiation-treated mice, suggesting that radiation is necessary to proceed from adenoma to cancer in thyroid carcinogenesis. Further, there is a tendency for higher incidence of carcinoma in LID + Radiation-treated cKO mice (4% for WT vs 11% for cKO, in progress). These results suggest that the loss of Nkx2-1 can promote adenoma formation induced by iodine-deficiency, and possibly facilitate carcinogenesis induced by LID + Radiation. In summary, our results suggest that NKX2-1 may function as a tumor suppressor in thyroid carcinogenesis. We are now trying to investigate the molecular mechanisms by which loss of NKX2-1 affects thyroid proliferation and facilitates neoplasm formation by examining the molecular profiles of mouse thyroids after LID and/or radiation treatment. Citation Format: Yo-Taro Shirai, Yoshinori Takizawa, Manabu Iwadate, Jorge Paiz, Shigetoshi Yokoyama, Masaaki Miyakoshi, Jerrold M. Ward, Shioko Kimura. Role of NKX2-1 in thyroid neoplasms induced by iodine-deficiency and radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2661.
Abstract 532: Association of pCR and the 8-gene signature: NRG Oncology/NSABP B-41
Authors: Nan Song, Xiaoqing E. Tan, Ying Wang, Rim S. Kim, Hanna Bandos, Gong Tang, Eleftherios Mamounas, Charles E. Geyer, Priya Rastogi, Samuel A. Jacobs, Ashok Srinivasan, Peter C. Lucas, Soonmyung Paik, Norman Wolmark, Sandra M. Swain, Katherine L. Pogue-Geile
Journal: Cancer Research (2021)

Abstract Background: Lapatinib (L), a HER2 signaling, tyrosine kinase inhibitor, demonstrated numerically higher pCR in NSABP B-41 when added to paclitaxel (AC→P) and trastuzumab (T) following doxorubicin + cyclophosphamide (62% v 52.5%). We previously validated an 8-gene signature that predicted the degree of T benefit in NSABP B-31 and NCCTG9831. The purpose of this study is to determine the association of pCR with the 8- gene T-benefit groups, enabling the possibility of stratifying patients (pts) who do or do not receive benefit from L. Methods: Normalized B-41 nCounter® Breast Cancer 360 gene expression data was used to define the three T-benefit groups: large-, moderate-, and no-. The 8-gene signature was modified to use only 7 genes because one of the 8 genes was not included in the nCounter code set. The ability of the 7-gene signature to predict T benefit was equivalent to the 8-gene signature when tested in B-31. Comparisons within each treatment arm were made with Fisher's exact test. Results: The pCR rates were significantly different among the three groups in the AC→P+T arm: Large: 24/28 (86%); Moderate: 13/32 (41%); and No: 1/9 (11%); p&amp;lt;0.001, but were not significantly different in the other two arms; a trend for significance was seen in the AC→P+T+L arm (Table 1). We also tested if L would improve pCR when added to AC→P+T in any of the 7-gene benefit groups compared to T. There was a non-significant, numerical increase in pCR in the no-benefit group in the AC→P+T+L arm (44%) v the AC→P+T arm (11%) (p=0.29). Conclusions: The significant association of the modified 8-gene benefit groups with pCR in the AC→P+T arm suggests this signature could identify pts who may benefit from dual HER2-targeted neoadjuvant therapy. This could be tested in a meta-analysis including other neoadjuvant trials. Support: Lombardi CCC; BCRF; GSK; P30CA051008; Genentech; NSABP Table 1.pCR rates in trastuzumab benefit groups in NSABP B-41pCR rates in Breast and NodesTreatmentNo BenefitIntermediateLarge BenefitEntire Cohortp valueAC→P+T1/9 (11.1%)13/32(40.6%)24/28 (85.7%)38/69 (55.1%)&amp;lt;0.001AC→P+L2/7 (28.6%)11/26 (42.3%)14/31 (45.2%)27/64 (42.2%)0.82AC→P+T+L4/9 (44.4%)11/25 (44.0%)20/27 (74.1%)35/61 (57.4%)0.051 Citation Format: Nan Song, Xiaoqing E. Tan, Ying Wang, Rim S. Kim, Hanna Bandos, Gong Tang, Eleftherios Mamounas, Charles E. Geyer, Priya Rastogi, Samuel A. Jacobs, Ashok Srinivasan, Peter C. Lucas, Soonmyung Paik, Norman Wolmark, Sandra M. Swain, Katherine L. Pogue-Geile. Association of pCR and the 8-gene signature: NRG Oncology/NSABP B-41 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 532.
Abstract 813: Clinical significance of pathogenic variants in germline BRCA1/2 wild type patients at risk for hereditary breast cancer
Authors: Xiaying Kuang, Nan Shao, Ying Lin
Journal: Cancer Research (2021)

Abstract Objectives: Approximately, 5-10% of breast cancer (BC) are related to inherited germline mutations. Homologous recombination repair (HRR) of DNA is the most important theory in hereditary cancer, in which BRCA1/2 are the most recognized and tested genes. Genetic testing for hereditary BC has changed significantly. Increasing evidence suggests parallel multigene testing of HRR gene. Methods: NGS-based germline multigene-panel testing of 105 HRR gene was performed on 159 high risk BC patients with at least one of the following risk factors: triple negative BC, early onset (≤45y), family history of BC and bilateral BC. Capture-base targeted sequencing was performed on white blood cells using a panel consisting of 105 genes related to homologous recombination repair of DNA. Results: Among the 159 patients of median age 40, All the patients had early stage infiltrating ductal carcinoma. 12 patients (7.55%) had pathogenic BRCA1/2 mutation. We investigated the prevalence of 21 pathogenic germline pathogenic mutations beyond BRCA1/2 from 21 patients spanning 13 HRR genes, resulting in a prevalence rate of 13.21% for pathogenic germline mutations in high risk germline BRCA1/2 WT BC patients. PALB2 is the most common gene with pathogenic mutation (n=5). In these 21 patients, 18 (85.71%) were diagnosed with BC before the age of 45, within 7 patients (33.33%) even younger than 35 years old. 7 of them (33.33%) had bilateral BC; one had triple negative BC (4.76%) and 5 patient (23.81%) had a family history of BC. Nearly half of the patients (n=9) presented at least 2 of the risk factors. Conclusions: Our study confirms the clinical significance of testing non-BRCA genes, and suggests multigene panel testing for patients at risk for hereditary BC as a routine in patients with those risk factors, especially young and bilateral BC patients even without family history of BC. Citation Format: Xiaying Kuang, Nan Shao, Ying Lin. Clinical significance of pathogenic variants in germline BRCA1/2 wild type patients at risk for hereditary breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 813.
Prospective multi centre registry for patients undergoing surgery for male stress urinary incontinence. An update of the EAU Registry ‘SATURN’
Authors: F.M.J. Martens, J. Heesakkers, F. Van Der Aa, O.J. Nilsen, K. Van Renterghem, R. Zachoval, L. De Kort, J. Romero-Otero, E. Sacco, N. Thiruchelvam, J.I. Martinez-Salamanca, A. Bjartell, C. Caris, R. Schipper, W. Witjes, R. Hamid
Journal: European Urology (2021)
Innovative therapeutic strategy for B-cell malignancies that combines obinutuzumab and cytokine-induced killer cells
Authors: Anna Dalla Pietà, Elisa Cappuzzello, Pierangela Palmerini, Annavera Ventura, Andrea Visentin, Giuseppe Astori, Katia Chieregato, Valentina Mozzo, Omar Perbellini, Maria Chiara Tisi, Livio Trentin, Carlo Visco, Marco Ruggeri, Roberta Sommaggio, Antonio Rosato
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Patients affected by aggressive B-cell malignancies who are resistant to primary or salvage chemoimmunotherapy have an extremely poor prognosis and limited therapeutic options. Promising therapeutic success has been achieved with the infusion of CD19 chimeric antigen receptor-T cells, but several limits still restrain the administration to a limited proportion of patients. This unmet clinical need might be fulfilled by an adoptive immunotherapy approach that combines cytokine-induced killer (CIK) cells and monoclonal antibodies (mAb) to the CD20 antigen. Indeed, CIK cells are an effector population endowed with antitumor activity, which can be further improved and antigen-specifically redirected by clinical-grade mAb triggering antibody-dependent cell-mediated cytotoxicity. Methods CIK cells were generated from peripheral blood of patients affected by different B-cell malignancies using a blinatumomab-based cell culture protocol. Effector cells were combined with the anti-CD20 mAb obinutuzumab and their therapeutic activity was assessed both in vitro and in vivo. Results CIK cells were successfully expanded in clinically relevant numbers, starting from small volumes of peripheral blood with extremely low CD3 + counts and high tumor burden. This relied on the addition of blinatumumab in culture, which leads to the simultaneous expansion of effector cells and the complete elimination of the neoplastic component. Moreover, CIK cells were highly cytotoxic in vitro against both B-cell tumor cell lines and autologous neoplastic targets, and had a significant therapeutic efficacy against a B-cell malignancy patient-derived xenograft on in vivo transfer. Conclusions The combination of an easily expandable CIK cell effector population with a mAb already in clinical use establishes a tumor antigen-specific redirection strategy that can be rapidly translated into clinical practice, providing an effective therapeutic alternative for B-cell malignancies without any need for genetic modifications. Additionally, the approach can be potentially applied to an extremely vast array of different tumors by simply substituting the targeting mAb.
Molecular Evolutionary Dynamics of Energy Limited Microorganisms
Authors: William R Shoemaker, Evgeniya Polezhaeva, Kenzie B Givens, Jay T Lennon
Journal: Molecular Biology and Evolution (2021)

Abstract Microorganisms have the unique ability to survive extended periods of time in environments with extremely low levels of exploitable energy. To determine the extent that energy limitation affects microbial evolution, we examined the molecular evolutionary dynamics of a phylogenetically diverse set of taxa over the course of 1,000 days. We found that periodic exposure to energy limitation affected the rate of molecular evolution, the accumulation of genetic diversity, and the rate of extinction. We then determined the degree that energy limitation affected the spectrum of mutations as well as the direction of evolution at the gene level. Our results suggest that the initial depletion of energy altered the direction and rate of molecular evolution within each taxon, though after the initial depletion the rate and direction did not substantially change. However, this consistent pattern became diminished when comparisons were performed across phylogenetically distant taxa, suggesting that although the dynamics of molecular evolution under energy limitation are highly generalizable across the microbial tree of life, the targets of adaptation are specific to a given taxon.
Global Crosstalk between Two Histone Modifications That Control Transcriptional Elongation in MLL Leukemia
Authors: Jiachen Bu, Aili Chen, Xiaomei Yan, Fuhong He, Yunzhu Dong, Yile Zhou, Jianlin He, Yoshihiro Hayashi, Di Zhan, Yanling Sun, Yue Zhang, Zhijian Xiao, Lee Grimes, Qianfei Wang, Gang Huang
Journal: Blood (2017)
Abstract LB170: HER2-targeted interferon-beta-1a mutein, a potent immunocytokine for the treatment of HER2-positive cancers
Authors: Chan Gyu Lee, Tae Eun Kim, Sungyoul Hong, Jongwan Chu, Ju Eun Kang, Hae Min Jeong, Young Kee Shin
Journal: Cancer Research (2021)

Abstract Background: Interferon beta (IFN-β), a promising potent cytokine, has been attracting attention for treatment of cancer. The pleiotropic antitumor effects of IFN-β have been studied, with specific reference to their direct role on cancer cells and indirect action through the immune effector cells. However, its systemic toxicities and poor biophysical properties prevent IFN-β from being widely used for cancer therapy. Since the potential of cytokine therapies are impaired due to dose-limiting systemic toxicities, novel treatment methods should be developed to safely deliver effective drug quantities at the tumor sites. Like antibody-drug conjugates (ADCs), immunocytokine can be attempted to induce cytokine's organ-targeting and alleviate its systemic side effects. Here, we designed recombinant IFN-β mutein immunocytokines that comprise a HER2-targeting antibody and IFN-β mutein, and evaluate the antitumor properties against HER2-positive cancers.Method: A panel of human gastric cancer cell lines was treated with trastuzumab-IFN-β mutein to evaluate direct antitumor effect. In addition, to test the immune cell-mediated antitumor effect, cancer cells were co-cultured with effector cells (e.g. PBMC) in the absence or drug. The antitumor efficacy of trastuzumab-IFN-β mutein in vivo was tested in HER2-positive cancer xenograft models using nude mice or humanized mice. Result: Trastuzumab-IFN-β mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-β mutein alone. Trastuzumab-IFN-β mutein also displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-β mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Moreover, trastuzumab-IFN-β mutein significantly suppress tumor growth in HER2-positive cancer xenograft models. Tumor-infiltration of lymphocytes was enhanced by trastuzumab-IFN-β mutein, implying that the tumor-targeting IFN-β may have an antitumor effect through increased immune response. Conclusion: We have characterized and evaluated the antitumor properties of trastuzumab-IFN-β mutein in HER2-expressing cancers. Since IFN-β activates antitumor immune responses, it is expected to be administered in combination with immunotherapeutic drugs. Therefore, the study suggests that trastuzumab-IFN-β mutein is a promising candidate for the treatment of HER2-positive carcinoma. Citation Format: Chan Gyu Lee, Tae Eun Kim, Sungyoul Hong, Jongwan Chu, Ju Eun Kang, Hae Min Jeong, Young Kee Shin. HER2-targeted interferon-beta-1a mutein, a potent immunocytokine for the treatment of HER2-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB170.
Abstract 2129: Usp22 controls multiple signaling pathways in development and disease
Authors: Evangelia Koutelou, Xianghong Kuang, Sharon Y. Dent
Journal: Cancer Research (2021)

Abstract Our research is focused on defining the functions of histone-modifying enzymes in normal cells so that we can understand how alterations in these activities contribute to tumor development or progression. The highly conserved SAGA complex plays important roles at multiple steps of gene transcription in yeast, flies, and mammalian cells. This modular complex houses two enzymatic activities, the GCN5 histone acetyltransferase, and the USP22 deubiquitinase. USP22 is overexpressed in highly aggressive, therapy-resistant cancers, but the normal functions of this deubiquitinase are not well defined. Our detailed analysis of the embryonic lethality observed in the Usp22-/- mouse model we generated highlighted a critical role for Usp22 in the developing placenta. We found that Usp22 deletion in mice results in embryonic lethality due to defects in the formation and organization of extra-embryonic placental tissues, culminating in failure to establish proper vascular interactions with the maternal circulatory system. These phenotypes arise from abnormal gene expression patterns that reflect defective kinase signaling, including TGFß and several receptor tyrosine kinase (RTK) pathways. Interestingly, overexpression of USP22 in mice leads to an over branching phenotype of the mammary gland, which is linked to the deregulation of the signaling pathways described above. Our results provide insights to potential angiogenic functions of the SAGA complex, indicate that Usp22 is critical for the proper execution of multiple signaling pathways important for normal development, and provide new clues towards Usp22 contributions to cancer and other disease states. Citation Format: Evangelia Koutelou, Xianghong Kuang, Sharon Y. Dent. Usp22 controls multiple signaling pathways in development and disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2129.