tbuckley/cabot-search huggingface dataset:
Implementing virtual mind-body programming to support cancer patients during COVID-19.
Authors: Jun J. J. Mao, Kin Wai (Tony) Hung, Nicholas Emard, Fernanda C. G. Polubriaginof, Kathleen Lynch, Thomas Michael Atkinson, Kelly Marie Trevino, Claus Jensen
Journal: Journal of Clinical Oncology (2021)

1585 Background: Despite growing evidence of mind-body therapies for physical and psychological health among patients with cancer, their access remains limited. The COVID-19 pandemic has further disrupted the delivery of necessary cancer and supportive care; thus, the need to support patients with cancer is unprecedented. To expand the reach and access of mind-body therapies, we developed, implemented, and evaluated a novel virtual mind-body program for patients with cancer. Methods: We rapidly developed a 7-day a week virtual mind-body program, Integrative Medicine at Home (IM@Home), for patients with cancer (ages ≥18 years) and deployed it on April 1 st , 2020. IM@Home included mind-body group therapy classes in fitness, meditation, yoga, dance, tai chi, and music delivered using Zoom video conferencing. Classes ranged from 30-45 minutes and were led by an integrative medicine clinician. Patients had the option to register for a 1-month, 3-month, or 6-month membership to gain unlimited access to all virtual mind-body classes. Multi-method evaluation was conducted using the RE-AIM conceptual framework to guide surveys and qualitative interviews. Surveys were analyzed using descriptive statistics and interviews were analyzed using grounded theory. Results: Between April 2020 and January 2021, IM@Home registered over 32,000 class participants, with a weekly average attendance of 700-800 participants. In a 4-month post-deployment survey (n = 131), nearly all participants were satisfied with IM@Home (93.9%) and would recommend the program to friends and family (95.4%). A majority of participants also found IM@Home to be simple to use (87.0%) and said the program had a variety of classes that interested them (93.1%). Three-quarters of participants (74.8%) were taking 3 to 7 classes a week (range: 1 to 15 classes), among which the most popular classes were fitness (88.7%), chair yoga (37.1%), and tai chi (33.1%). Most participants preferred a 3-month membership (51.6%), followed by a 6-month membership (19.5%). In qualitative interviews (n = 30), participants reported IM@Home helped them to: 1) maintain structured routines and stay motivated to exercise; 2) cope with COVID-19-related and cancer-related stressors; and 3) connect with their fellow cancer patient community and foster social relationships during a time of isolation. Conclusions: Virtual mind-body programming, through IM@Home, reached many patients with cancer to address their physical and psychological challenges during COVID-19. As patients with cancer experience high physical and psychological symptom burden following diagnosis, future clinical trials are needed to evaluate the specific effects of IM@Home when integrated into active treatment and survivorship care.
A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.
Authors: Ying Cheng, Ying Liu, Jinhua Xu, Jing Zhu, Ying Wang, Ying Xin, Yanping Wang, Chunjiao Wu, Hongxia Cui, Xianhong Liu, Jixin Dai, Zili Li, XiangHua Zhang, Jing Zhang, Ben Zhang
Journal: Journal of Clinical Oncology (2021)

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade&gt;=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade&gt;=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.
MosaicNeedles: A tool for multi-omic liquid biopsy sensitivity and specificity enhancement.
Authors: Qimin Quan, Joe Wilkinson, Joshua Ritchey, Alaina Kaiser, John Geanacopoulos, John Boyce
Journal: Journal of Clinical Oncology (2021)

e15019 Background: Liquid biopsy has evolved to be an important method complementary to tissue biopsy. It is not only non-invasive, but also has the potential to detect cancer in its earliest stages and monitor patients in remission. The integration of proteomics into liquid biopsy may transform the molecular diagnostics of cancer and accelerate basic and clinical oncology research. A recent study showed that adding just 8 protein biomarkers to a panel of circulating DNA biomarkers increased the diagnostic accuracy up to 98% sensitivity and 99% specificity. Proteomics also bridges the gaps of functional information lost due to post-transcriptional and post-translational modifications in the genomic approach. However, the proteogenomic approach normally requires the use of multiple different assay technologies and laboratory workflows, including mass spectrometry. Methods: NanoMosaic’s Tessie platform employs a densely integrated nanoneedle sensor array (thus named MosaicNeedles) which can be used to detect both nucleic acids and proteins in a single assay process with reduced workflow complexity, without the need for mass spectrometry. Results: The NanoMosaic platform is a label-free, digital, single molecule counting technology using nanoneedles. It achieves sub-pg/ml (̃fM) level sensitivity with 7 logs of dynamic range. An array of nanoneedles is densely integrated and manufactured with CMOS-compatible nanofabrication processes. Each nanoneedle is a single molecule biosensor that is functionalized with capture probes. The capture probe can be either an antibody for protein detection or an oligonucleotide with a specific target sequence to a DNA fragment, mRNA, or miRNA of interest. The scattering spectrum of each nanoneedle changes when an analyte binds to its surface. At low abundance, analytes that are captured can be quantitated by counting the presence or absence of a color change on each individual nanoneedle in a binary fashion. As an analyte concentration increases the binding events increase accordingly and achieve saturation. In this range, an analog analysis on the spectrum shift will be performed, thus providing a wider dynamic range, up to 7 logs. Ultrahigh level multiplex can be achieved by parallelizing each analyte specific sensing area without loss of sensitivity or dynamic range. A 10,000-plex study can be achieved with a total of 2.5 billion nanoneedles on a 50mm by 50mm consumable. In this consumable, a 2,000-plex proteome and 8,000 cell-free DNA fragments can be detected. Conclusions: In conclusion, a full proteogenomic quantification can be performed on the NanoMosaic platform in one reaction, with higher sensitivity, lower cost and higher throughput than is currently possible by traditional methods. In addition, the high-plexibility of the NanoMosaic platform allows the discovery of new biomarkers across the whole proteome without the need for mass spectrometry.
The circACTN4 interacts with FUBP1 to promote tumorigenesis and progression of breast cancer by regulating the expression of proto-oncogene MYC
Authors: Xiaosong Wang, Lei Xing, Rui Yang, Hang Chen, Min Wang, Rong Jiang, Luyu Zhang, Junxia Chen
Journal: Molecular Cancer (2021)

Abstract Background Recent studies have revealed that circular RNAs (circRNAs) play significant roles in the occurrence and development of many kinds of cancers including breast cancer (BC). However, the potential functions of most circRNAs and the molecular mechanisms underlying progression of BC remain elusive. Method Here, Circular RNA microarray was executed in 4 pairs of breast cancer tissues and para-cancer tissues. The expression and prognostic significance of circACTN4 in BC cells and tissues were determined by qRT-PCR and in situ hybridization. Gain-and loss-of-function experiments were implemented to observe the impacts of circACTN4 on the growth, invasion, and metastasis of BC cells in vitro and in vivo. Mechanistically, chromatin immunoprecipitation, luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation, fluorescence in situ hybridization and co-immunoprecipitation assays were executed. Results CircACTN4 was significantly upregulated in breast cancer tissues and cells, its expression was correlated with clinical stage and poor prognosis of patients with BC. Ectopic expression of circACTN4 strikingly facilitated the growth, invasion, and metastasis of breast cancer cells in vitro and in vivo. Whereas knockdown of circACTN4 revealed opposite roles. CircACTN4 was mainly distributed in the nucleus. Further mechanistic research proved that circACTN4 could competitively bind to far upstream element binding protein 1 (FUBP1) to prevent the combination between FUBP1 and FIR, thereby activating MYC transcription and facilitating tumor progression of breast cancer. Furthermore, we found that upstream transcription factor 2 (USF2) might promote the biogenesis of circACTN4. Conclusion Our findings uncover a pivotal mechanism that circACTN4 mediated by USF2 might interact with FUBP1 to promote the occurrence and development of breast cancer via enhancing the expression of MYC. CircACTN4 could be a novel potential target for diagnosis and treatment of breast cancer.
Enhancer Hijacking Drives Oncogenic <i>BCL11B</i> Expression in Lineage-Ambiguous Stem Cell Leukemia
Authors: Lindsey E. Montefiori, Sonja Bendig, Zhaohui Gu, Xiaolong Chen, Petri Pölönen, Xiaotu Ma, Alex Murison, Andy Zeng, Laura Garcia-Prat, Kirsten Dickerson, Ilaria Iacobucci, Sherif Abdelhamed, Ryan Hiltenbrand, Paul E. Mead, Cyrus M. Mehr, Beisi Xu, Zhongshan Cheng, Ti-Cheng Chang, Tamara Westover, Jing Ma, Anna Stengel, Shunsuke Kimura, Chunxu Qu, Marcus B. Valentine, Marissa Rashkovan, Selina Luger, Mark R. Litzow, Jacob M. Rowe, Monique L. den Boer, Victoria Wang, Jun Yin, Steven M. Kornblau, Stephen P. Hunger, Mignon L. Loh, Ching-Hon Pui, Wenjian Yang, Kristine R. Crews, Kathryn G. Roberts, Jun J. Yang, Mary V. Relling, William E. Evans, Wendy Stock, Elisabeth M. Paietta, Adolfo A. Ferrando, Jinghui Zhang, Wolfgang Kern, Torsten Haferlach, Gang Wu, John E. Dick, Jeffery M. Klco, Claudia Haferlach, Charles G. Mullighan
Journal: Cancer Discovery (2021)

Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. SIGNIFICANCE: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries.This article is highlighted in the In This Issue feature, p. 2659.
HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease
Authors: Jing Zhang, Yaowu Qin, Mireya Martinez, Miguel Flores-Bellver, Murilo Rodrigues, Aumreetam Dinabandhu, Xuan Cao, Monika Deshpande, Yu Qin, Silvia Aparicio-Domingo, Yuan Rui, Stephany Y. Tzeng, Shaima Salman, Jin Yuan, Adrienne W. Scott, Jordan J. Green, M. Valeria Canto-Soler, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi
Journal: Journal of Clinical Investigation (2021)

Therapies targeting VEGF have proven only modestly effective for the treatment of proliferative sickle cell retinopathy (PSR), the leading cause of blindness in patients with sickle cell disease. Here, we shift our attention upstream from the genes that promote retinal neovascularization (NV) to the transcription factors that regulate their expression. We demonstrated increased expression of HIF-1α and HIF-2α in the ischemic inner retina of PSR eyes. Although both HIFs participated in promoting VEGF expression by hypoxic retinal Müller cells, HIF-1 alone was sufficient to promote retinal NV in mice, suggesting that therapies targeting only HIF-2 would not be adequate to prevent PSR. Nonetheless, administration of a HIF-2–specific inhibitor currently in clinical trials (PT2385) inhibited NV in the oxygen-induced retinopathy (OIR) mouse model. To unravel these discordant observations, we examined the expression of HIFs in OIR mice and demonstrated rapid but transient accumulation of HIF-1α but delayed and sustained accumulation of HIF-2α; simultaneous expression of HIF-1α and HIF-2α was not observed. Staggered HIF expression was corroborated in hypoxic adult mouse retinal explants but not in human retinal organoids, suggesting that this phenomenon may be unique to mice. Using pharmacological inhibition or an in vivo nanoparticle-mediated RNAi approach, we demonstrated that inhibiting either HIF was effective for preventing NV in OIR mice. Collectively, these results explain why inhibition of either HIF-1α or HIF-2α is equally effective for preventing retinal NV in mice but suggest that therapies targeting both HIFs will be necessary to prevent NV in patients with PSR.
生体異物輸送体Mdr1は腸胆汁酸の存在下でのT細胞恒常性を強化する【Powered by NICT】
Authors: Cao Wei, Kayama Hisako, Chen Mei Lan, Delmas Amber, Sun Amy, Kim Sang Yong, S Rangarajan Erumbi, McKevitt Kelly, P Beck Amanda, B Jackson Cody, Crynen Gogce, Oikonomopoulos Angelos, N Lacey Precious, J Martinez Gustavo, Izard Tina, G Lorenz Robin, Rodriguez-Palacios Alex, Cominelli Fabio, T Abreu Maria, W Hommes Daniel, B Koralov Sergei, Takeda Kiyoshi, S Sundrud Mark
Journal: Immunity (2017)
Application of RSClin to guide treatment recommendations for premenopausal patients with early-stage hormone-positive breast cancer and intermediate risk oncotype recurrence scores.
Authors: Brittney Shulman Zimmerman, Shana Berwick, Alaina J Kessler, Danielle Seidman, Sara Malin Hovstadius, Erin Moshier, Julia Blanter, Asem Berkalieva, Shabnam Jaffer, Natalie F Berger, Krystal Pauline Cascetta, Amy Tiersten
Journal: Journal of Clinical Oncology (2021)

e12511 Background: The RSClin model, which incorporates the Oncotype Recurrence Score (RS) and clinicopathologic features, was recently developed to further tailor prognosis and prediction of chemotherapy benefit for patients with early-stage hormone positive (HR+) breast cancer (BC) (Sparano et al, 2020). The RSClin calculator is available online to assist treatment planning for situations where chemotherapy benefit is uncertain. Covariates include Oncotype RS, tumor grade, tumor size and patient age. The risk calculator generates a 10-year distant recurrence risk and absolute chemotherapy benefit. This tool may be especially helpful to determine treatment management for premenopausal patients with early-stage HR+ BC with intermediate risk (IR) Oncotype RS (16-25). We retrospectively applied RSClin to this patient population to determine if it would have changed treatment recommendations. Methods: We identified premenopausal women with node-negative early-stage BC with IR RS (16-25) within our large Oncotype database. Using the RSClin model, we selected &gt;5% absolute chemotherapy benefit as a reasonable cutoff to recommend chemotherapy. We compared the treatment recommendation based on RSClin with the treatment previously recommended by breast oncologists at our large academic medical center in New York City. Results: There were 86 patients who met criteria with a median age of 46 years. Of these, 26 patients (30%) were recommended chemotherapy plus endocrine therapy (ET) and 60 (70%) were recommended ET alone. After applying the RSClin model (data available for 83/86 patients), 19 (23%) would have resulted in a change in treatment recommendation and 64 (77%) would have remained unchanged. Overall, 8 (10%) would have withheld chemotherapy when it was previously offered and 11 (13%) would have recommended chemotherapy when it was previously excluded. There were 8 (9%) secondary invasive breast events in this population, with 2 (2%) being ipsilateral, 3 (3%) being contralateral and 3 (3%) metastatic at a median follow up of 46.9 months. Conclusions: The RSClin model would have changed management of premenopausal patients with IR RS in 23% of patients. This model, although not yet prospectively validated, may help individualize therapy for patients with less definitive treatment plans. Using RSClin, we can aim to minimize recurrence rates and avoid unnecessary chemotherapy in selected patients. This model is easy to apply and will have important clinical utility moving forward.
Real-world data analysis of the utilization of second-line maintenance therapy for patients with advanced ovarian cancer.
Authors: Robert Lawrence Reid, Yiqiong Xie, Junxin Shi, Katrine L Wallace
Journal: Journal of Clinical Oncology (2021)

e18702 Background: Although ovarian cancer (OC) represents about 1% of all new cancer cases in the US, it is the 5th leading cause of cancer death among women. Several maintenance therapies have been introduced (ie, bevacizumab and poly[ADP-ribose] polymerase inhibitors [PARPi]) to extend the time between chemotherapy and relapse (ie, progression-free survival) in this population. Both bevacizumab and PARPi have been recommended as second-line (2L) maintenance treatment by the National Comprehensive Cancer Network for OC patients (pts) with and without BRCA alterations since 2013 and 2017, respectively. We present recent estimates of 2L maintenance utilization. Methods: From the iKnowMed electronic health record database of the US Oncology Network, which includes 1,200 physicians operating in over 470 sites of care in the US, adult females were included if diagnosed with advanced OC, received a 2L platinum-containing regimen for advanced OC, and had ≥2 visits within the database between 1 Jan 2016 and 31 July 2020. Pts were followed longitudinally until 31 Oct 2020, the last pt record, or date of death, whichever occurred earliest. Rates of 2L maintenance therapy (ie, bevacizumab monotherapy or PARPi following discontinuation of 2L platinum-based chemotherapy) were determined for 1) all pts, 2) pts with a BRCA1 or BRCA2 gene alteration (BRCA+), and 3) pts without a BRCA alteration (BRCA-). Results: 11,494 pts were identified with a diagnosis of advanced OC; of those, 1,051 met the study inclusion criteria. Median age at advanced OC diagnosis was 64.2 years. Median follow-up time from discontinuation of 2L platinum chemotherapy until the end of observation was 24.6 mo. Of 1,051 pts who received 2L platinum-based chemotherapy, 513 (49%) subsequently received maintenance therapy (271 [26%] PARPi, 294 [28%] bevacizumab, 32 [3%] a non-platinum chemotherapy) and 538 (51%) did not receive maintenance (ie, underwent “active surveillance”). The proportion of eligible pts receiving 2L maintenance did not increase over the study period, with 53%, 58%, and 56% of pts receiving 2L maintenance versus 47%, 42%, and 44% of pts undergoing active surveillance in the years 2017, 2018, and 2019, respectively. Among the 1,051 pts who received 2L platinum chemotherapy, 662 pts had a documented BRCA test result (94 [14%] BRCA+, 568 [86%] BRCA-). Among BRCA+ pts, 67% received 2L maintenance, while BRCA- pts received significantly less maintenance treatment (53%, p = 0.0104). Conclusions: Despite having several treatment options available for 2L advanced OC maintenance, fewer than half of eligible pts receive maintenance treatment. Although the utilization rate was higher among pts with BRCA alterations versus those without, our data suggest that there is a significant proportion of eligible pts who are not receiving maintenance therapy despite treatment guideline recommendations.