tbuckley/cabot-search huggingface dataset:
Expression and pharmacologic inhibition of the anti-apoptotic Bcl-2 family members in feline tumor cell lines
Authors: Michael Huelsmeyer, Jessica MacDonald, Douglas Thamm, David Vail
Journal: Cancer Research (2008)

4391  Spontaneous tumors in companion animals offer a promising opportunity as models for human cancer biology and translational therapeutics. Feline oral squamous cell carcinomas (OSCC) and soft tissue sarcomas (STS) are excellent examples of spontaneous tumors that arise in companion animals that share similar biologic behavior and clinical outcome when compared to their human counterparts. Here, we report that the anti-apoptotic proteins Bcl-2, Bcl-xL and Bcl-w may play an important role in the survival of feline OSCC and STS cells and that inhibition of this family of proteins by ABT-737, a small molecule inhibitor that targets the Bcl-2 family, leads to cell death in vitro. More importantly, we show that inhibition of these Bcl-2 family members by ABT-737 leads to chemosensitization of OSCC and STS cells and enhances the effects of certain chemotherapies. In this study, the feline OSCC cell line SCCF-1 and four feline STS cell lines (Tietz, Ela-1, Kai and Ham) were examined for expression of Bcl-2, Bcl-xL and Bcl-w via western blot analysis. All three of the Bcl-2 family members were expressed in all of the STS cell lines tested. Interestingly, the OSCC cell line SCCF-1 had undetectable levels of Bcl-2 and low expression of Bcl-w when compared to the panel of STS cell lines. OSCC did however have significantly higher expression of the Bcl-xL compared to STS cell lines. After determining that at least one of the Bcl-2 family members was expressed in the OSCC and STS cell lines, we examined the effect of ABT-737 on the cell lines in vitro. Cells were incubated with increasing amounts of ABT-737 for 72 hours and analyzed using a colorimetric proliferation assay. The results showed that ABT-737 was able to inhibit cell growth in OSCC cells and 3 of the 4 STS cell lines by greater that 75% when concentrations reached 20 μM. SCCF-1, Ela-1, Ham, and Kai showed greater than 50% growth inhibition with concentrations between 1 μM and 5 μM ABT-737 in minimal growth media containing 1% fetal bovine serum (MEM-1%). Staining of the cells with annexin-FITC and propidium iodide indicated that the inhibitory effect of ABT-737 is a result of apoptosis and not growth arrest. SCCF-1 (OSCC) and Ela-1 (STS) cells were then incubated in MEM-1% with 1 μM ABT-737 and increasing levels of the chemotherapeutic drugs doxorubicin (DOX) and carboplatin (CPT). The results showed that ABT-737 was able to sensitize the cells to the effects of both DOX and CPT. The information gained from these studies leads us to believe that the use of ABT-737 in combination with conventional chemotherapeutic agents may improve the clinical outcome of cats with OSCC or STS.
Modulating autophagic flux via ROS-responsive targeted micelles to restore neuronal proteostasis in Alzheimer's disease
Authors: Shuting Xu, Peng Yang, Kang Qian, Yixian Li, Qian Guo, Pengzhen Wang, Ran Meng, Jing Wu, Jinxu Cao, Yunlong Cheng, Minjun Xu, Qizhi Zhang
Journal: Bioactive Materials (2021)

Compromised autophagy and defective lysosomal clearance significantly contribute to impaired neuronal proteostasis, which represents a hallmark of Alzheimer's disease (AD) and other age-related neurodegenerative disorders. Growing evidence has implicated that modulating autophagic flux, instead of inducing autophagosome formation alone, would be more reliable to rescue neuronal proteostasis. Concurrently, selectively enhancing drug concentrations in the leision areas, instead of the whole brain, will maximize therapeutic efficacy while reduing non-selective autophagy induction. Herein, we design a ROS-responsive targeted micelle system (TT-NM/Rapa) to enhance the delivery efficiency of rapamycin to neurons in AD lesions guided by the fusion peptide TPL, and facilitate its intracellular release via ROS-mediated disassembly of micelles, thereby maximizing autophagic flux modulating efficacy of rapamycin in neurons. Consequently, it promotes the efficient clearance of intracellular neurotoxic proteins, β-amyloid and hyperphosphorylated tau proteins, and ameliorates memory defects and neuronal damage in 3 × Tg-AD transgenic mice. Our studies demonstrate a promising strategy to restore autophagic flux and improve neuronal proteostasis by rationally-engineered nano-systems for delaying the progression of AD.
Impressive Rapid Complete Response on FDG PET/CT to BRAF Inhibitors in a Metastatic Melanoma With Massive Tumor Burden
Authors: Ronan Abgral, Pierre-Yves Salaun, Bruno Sassolas
Journal: Clinical Nuclear Medicine (2021)

Recent advances in the development of innovative treatments for MM (metastatic melanoma) significantly improved survival. BRAF inhibitor-targeted therapies are also indicated in stage IV BRAF-mutant melanoma, especially dabrafenib and trametinib in combination. The authors present here an impressive rapid (1 month) complete metabolic response on FDG PET/CT to BRAF inhibitors of an MM with a massive tumor burden estimated at more than 10 kg.
1341P NRAS mutated non-small cell lung cancer (NSCLC) patients: Characteristics and outcomes
Authors: A. Dehem, J. Mazieres, A. Chour, F. Guisier, M. Ferreira, M. Boussageon, N. Girard, D. Moro-Sibilot, J. Cadranel, G. Zalcman, C. Ricordel, M. Wislez, C. Munck, C-H. Poulet, C. Gauvain, C. Descarpentries, E. Wasielewski, A.B. Cortot, S. Baldacci
Journal: Annals of Oncology (2021)
264P AMEERA-1: Subgroup analyses of phase I/II study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC)
Authors: S. Chandarlapaty, H.M. Linden, P. Neven, K. Petrakova, A. Bardia, P. Kabos, S. Braga, V. Boni, V. Pelekanou, N. Ternès, A. Gosselin, M. Celanovic, P. Cohen, G. Paux, M. Campone
Journal: Annals of Oncology (2021)
Biological data annotation via a human-augmenting AI-based labeling system
Authors: Douwe van der Wal, Iny Jhun, Israa Laklouk, Jeff Nirschl, Lara Richer, Rebecca Rojansky, Talent Theparee, Joshua Wheeler, Jörg Sander, Felix Feng, Osama Mohamad, Silvio Savarese, Richard Socher, Andre Esteva
Journal: npj Digital Medicine (2021)

Abstract Biology has become a prime area for the deployment of deep learning and artificial intelligence (AI), enabled largely by the massive data sets that the field can generate. Key to most AI tasks is the availability of a sufficiently large, labeled data set with which to train AI models. In the context of microscopy, it is easy to generate image data sets containing millions of cells and structures. However, it is challenging to obtain large-scale high-quality annotations for AI models. Here, we present HALS (Human-Augmenting Labeling System), a human-in-the-loop data labeling AI, which begins uninitialized and learns annotations from a human, in real-time. Using a multi-part AI composed of three deep learning models, HALS learns from just a few examples and immediately decreases the workload of the annotator, while increasing the quality of their annotations. Using a highly repetitive use-case—annotating cell types—and running experiments with seven pathologists—experts at the microscopic analysis of biological specimens—we demonstrate a manual work reduction of 90.60%, and an average data-quality boost of 4.34%, measured across four use-cases and two tissue stain types.
The evolution of music: One trait, many ultimate-level explanations
Authors: Edgar Dubourg, Jean-Baptiste André, Nicolas Baumard
Journal: Behavioral and Brain Sciences (2021)

Abstract We propose an approach reconciling the ultimate-level explanations proposed by Savage et al. and Mehr et al. as to why music evolved. We also question the current adaptationist view of culture, which too often fails to disentangle distinct fitness benefits.
Transurethral endoscopic retrograde pancreatography: a novel endoscopic technique to treat complications after pancreas transplantation
Authors: Mihajlo Gjeorgjievski, Abdelhai Abdelqader, Avik Sarkar, Haroon Shahid, Amy Tyberg, Michel Kahaleh
Journal: Endoscopy (2021)

In patients with transplanted pancreas, early technical failure accounts for more than half of graft losses during the initial posttransplant period – a complication that necessitates graft pancreatectomy [1]. Failure rates for pancreas recipients in the United States approximate 5 %, with reoperative rates between 12 % and 43 % [2] [3]. Graft thrombosis is the leading cause of technical failure, followed by anastomotic leak, infection, pancreatitis, and bleeding. The etiology of transplant pancreas leak may be a failure of healing/sealing of a pancreaticoenteric anastomosis, or a parenchymal disruption originating from the pancreatic ductal system [4]. Initial management of postoperative leaks involves percutaneous drainage. If clinical deterioration occurs, relaparotomy is mandatory [5]. Endoscopic retrograde pancreatography (ERP) offers pancreatic sphincterotomy and placement of pancreatic ductal stents, which are effective in treating pancreatic leaks. The postsurgical anatomy and its anastomosis with the bladder makes conventional endoscopic access impossible.
1632P At home androgen deprivation therapy for patients with prostate cancer during the COVID-19 pandemic. One center experience
Authors: T. Esakia, T. Melkadze, K. Tsiklauri, E. Mariamidze, S. Tsitsilashvili, N. Otkhozoria, M. Abuladze, N. Jokhadze, N. Balanchivadze
Journal: Annals of Oncology (2021)
Health-related Quality of Life for Patients Undergoing Radical Cystectomy: Results of a Large Prospective Cohort
Authors: Matthew B. Clements, Thomas M. Atkinson, Guido M. Dalbagni, Yuelin Li, Andrew J. Vickers, Harry W. Herr, S. Machele Donat, Jaspreet S. Sandhu, Daniel S. Sjoberg, Amy L. Tin, Bruce D. Rapkin, Bernard H. Bochner
Journal: European Urology (2021)
185P Receipt of neoadjuvant treatment (NADJ) and impact of types of surgery on health-related quality of life (HRQoL) among patients (pts) with early stage HR+/HER2- breast cancer (BC)
Authors: A. Rider, B. Bennett, R. Williams, L. Gillespie-Akar, A. Gogate
Journal: Annals of Oncology (2021)
PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma
Authors: Fengjie Liu, Yumei Gao, Bufang Xu, Shan Xiong, Shengguo Yi, Jingru Sun, Zhuojing Chen, Xiangjun Liu, Yingyi Li, Yuchieh Lin, Yujie Wen, Yao Qin, Shuxia Yang, Hang Li, Trilokraj Tejasvi, Lam Tsoi, Ping Tu, Xianwen Ren, Yang Wang
Journal: Blood (2021)

Abstract Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergo large-cell transformation (LCT) in the late stage, manifesting aggressive behavior, resistance to treatments, and poor prognosis, but the mechanisms involved remain unclear. To identify the molecular driver of LCT, we collected tumor samples from 133 MF patients and performed whole-transcriptome sequencing on 49 advanced-stage MF patients, followed by integrated copy number inference and genomic hybridization. Tumors with LCT showed unique transcriptional programs and enriched expressions of genes at chr7q. Paternally expressed gene 10 (PEG10), an imprinted gene at 7q21.3, was ectopically expressed in malignant T cells from LCT, driven by 7q21.3 amplification. Mechanistically, aberrant PEG10 expression increased cell size, promoted cell proliferation, and conferred treatment resistance by a PEG10/KLF2/NF-κB axis in in vitro and in vivo models. Pharmacologically targeting PEG10 reversed the phenotypes of proliferation and treatment resistance in LCT. Our findings reveal new molecular mechanisms underlying LCT and suggest that PEG10 inhibition may serve as a promising therapeutic approach in late-stage aggressive T-cell lymphoma.
727P Phase Ib INEOV neoadjuvant trial of the anti-PDL1, durvalumab (D) +/- anti-CTLA4 tremelimumab (T) with platinum chemotherapy for patients (pts) with unresectable ovarian cancer (OC): A GINECO study
Authors: A. Leary, T. De La Motte Rouge, A. Lortholary, B. Asselain, J. Alexandre, A. Floquet, A.M. Savoye, L. Chardin, N. Delanoy, C. Gavoille, B. You, V. D'Hondt, J. Grenier, C. Genestie, E. Pujade-Lauraine
Journal: Annals of Oncology (2021)
Detecting Selection in Multiple Populations by Modeling Ancestral Admixture Components
Authors: Jade Yu Cheng, Aaron J Stern, Fernando Racimo, Rasmus Nielsen
Journal: Molecular Biology and Evolution (2021)

One of the most powerful and commonly used approaches for detecting local adaptation in the genome is the identification of extreme allele frequency differences between populations. In this article, we present a new maximum likelihood method for finding regions under positive selection. It is based on a Gaussian approximation to allele frequency changes and it incorporates admixture between populations. The method can analyze multiple populations simultaneously and retains power to detect selection signatures specific to ancestry components that are not representative of any extant populations. Using simulated data, we compare our method to related approaches, and show that it is orders of magnitude faster than the state-of-the-art, while retaining similar or higher power for most simulation scenarios. We also apply it to human genomic data and identify loci with extreme genetic differentiation between major geographic groups. Many of the genes identified are previously known selected loci relating to hair pigmentation and morphology, skin, and eye pigmentation. We also identify new candidate regions, including various selected loci in the Native American component of admixed Mexican-Americans. These involve diverse biological functions, such as immunity, fat distribution, food intake, vision, and hair development.
522P Risk mitigation of ocular toxicities due to antibody drug conjugates (ADCs) in novel early-phase clinical trials
Authors: K. Chandran, R. Grochot, S. Lai, M.E. Timon, A. Sharp, A. Minchom, U. Banerji, J. de Bono, P. Ursell, J. Lopez
Journal: Annals of Oncology (2021)
1061P Safety of cemiplimab for advanced cutaneous squamous cell carcinoma: The Spanish named patient programme
Authors: A. Garcia Castano, E. Muñoz Couselo, A. Soria, J. Lavernia, O. Sanmartin, J. Cañueto, P. Ayala de Miguel, S. Beá Ardébol, L. Bellido Hernández, R. Fernández-de-Misa Cabrera, A.J. Cunquero-Tomás, L. Fernández Franco, A. Férnandez-Freire Leal, K. Mujika Eizmendi, C. Ortiz, P. Redondo, I. Romero, M. Serrano Fernández, J. Medina Martínez
Journal: Annals of Oncology (2021)
1583P COVID-19 related risk in patients enrolled in early-phase clinical trials
Authors: P. D'Amico, P. Trillo, S. Morganti, C. Corti, G. Vivanet, E. Crimini, L. Ascione, P. Tarantino, G. Antonarelli, M. Locatelli, A. Esposito, C. Belli, G. Curigliano
Journal: Annals of Oncology (2021)
LBA66 Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: Results from the EORTC-ETOP NIVOTHYM phase II trial
Authors: N. Girard, S. Ponce Aix, S. Cedres, T. Berghmans, S. Burgers, A.C. Toffart, S. Popat, A. Janssens, R. Gervais, M. Hochstenbag, M. Silva, I. Burger, H. Prosch, R.A. Stahel, A-S. Govaerts, A. Pochesci, A. Neven, S. Peters
Journal: Annals of Oncology (2021)
Health Care for Our Nation's Veterans: A Policy Paper From the American College of Physicians
Authors: Ryan Crowley, Omar Atiq, David Hilden, Thomas G. Cooney
Journal: Annals of Internal Medicine (2021)

The Veterans Health Administration (VHA) is the United States' largest integrated health care delivery system, serving over 9 million enrollees at nearly 1300 health care facilities. In addition to providing health care to the nation's military veterans, the VHA has a research and development program, trains thousands of medical residents and other health care professionals, and conducts emergency preparedness and response activities. The VHA has been celebrated for delivering high-quality care to veterans, early adoption of electronic medical records, and high patient satisfaction. However, the system faces challenges, including implementation of an expanded community care program, modernization of its electronic medical records system, and providing care to a population with complex needs. The position paper offers policy recommendations on VHA funding, the community care program, medical and health care professions training, and research and development.
689P Human leukocyte antigen (HLA) class I/II expression as a predictive biomarker for response to immune oncology (IO) therapy in metastatic clear-cell renal cell carcinoma (m-ccRCC)
Authors: L. Kinget, E. Roussel, D. Lambrechts, B. Boeckx, A.T.L. Verbiest, J. Zucman-Rossi, G. Couchy, C. Dalban, M. Meylan, S. Chabaud, Y. Vano, C. Sautès-Fridman, W-H. Fridman, M. Baldewijns, M. Albersen, N. Rioux-Leclercq, F. Tantot, N. Chaput, B. Beuselinck, L. Albiges
Journal: Annals of Oncology (2021)
719TiP SunRISe-1: Phase IIb study of TAR-200 in combination with cetrelimab (CET), TAR-200 alone, or CET alone in participants with high risk non-muscle invasive bladder cancer unresponsive to intravesical bacillus Calmette-Guérin who are ineligible for or elected not to undergo radical cystectomy
Authors: M.S. van der Heijden, C. Cutie, M. Acharya, K. Stromberg, X. Li, N. Beeharry, R. Stewart, J. Maffeo, C. Indoria, W. Levin, J. Jacob
Journal: Annals of Oncology (2021)
975P Impact of body mass index on the efficacy of immune checkpoint inhibitors in cancer
Authors: A. Rios Hoyo, M. Hardy-Werbin, X. Monzonís, I. Monge Escartin, L. Moliner, N. Navarro, Á. Taus, X. Durán, D. Conde, E. Arriola
Journal: Annals of Oncology (2021)
766P Mapping BRCA1/2 variants in ovarian cancer patients: Contribution of a BRCA2 founder effect
Authors: T. Duarte, S. Fragoso, P. Antunes Meireles, I.C. Oliveira, P. Rodrigues, C. Bexiga, B. Mira, A. Opinião, A.C. Luís, I. Miguel, S. Bento, F. Vaz, S. Santos
Journal: Annals of Oncology (2021)
LBA52 Sintilimab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced or metastatic esophageal squamous cell cancer: First results of the phase III ORIENT-15 study
Authors: L. Shen, Z-H. Lu, J-Y. Wang, Y-Q. Shu, L. Kong, L. Yang, B-H. Wang, Z-W. Wang, Y-H. Ji, G-C. Cao, H. Liu, T-J. Cui, N. Li, W-S. Qiu, Z. Ma, Y-L. Chen, H-Y. Li, X. Sun, Y. Wang, H. Zhou
Journal: Annals of Oncology (2021)
1539P Sarcomas in the Dutch LFS population: Data from the national screening of TP53 germline mutation carriers at the Netherlands Cancer Institute
Authors: G.F. de Wit, M.W.G. Ruijs, E.M.A. Bleiker, M.A. Kuenen, W.J. Van Houdt, B.C. Heeres, G.S. Sonke, W.T.A. Van Der Graaf
Journal: Annals of Oncology (2021)
Covid-19, climate change, and the environment: a sustainable, inclusive, and resilient global recovery
Authors: Nicholas Stern, IG Patel, Bob Ward
Journal: BMJ (2021)

We are at a critical moment in history, facing growing crises in climate change, biodiversity, and environmental degradation—as well as covid-19. But we also have an enormous opportunity to transform the global economy and usher in an era of greater wellbeing and prosperity, write <b>Nick Stern</b> and <b>Bob Ward</b>
Abstract 3193: First Preclinical Study of a New F-18 Labeled PET Tracer for Myocardial Perfusion Imaging
Authors: Marc Huisman, Takahiro Higuchi, Sybille Reder, Stephan Nekolla, Thorsten Poethko, David Casebier, Markus Schwaiger
Journal: Circulation (2007)

Introduction: An F-18 based myocardial perfusion imaging (MPI) tracer would increase the availability of tracers for cardiac PET/CT exams at stand-alone PET facilities. Hypothesis: F-18 labeled BMS-747158 – 02 is a promising tracer for MPI. Methods: All studies were carried out in healthy male Wistar rats (275 ± 25 g). The biodistribution of F-18 BMS-747158 – 02 was obtained 10 and 60 minutes post injection (p.i.). The first pass extraction fraction of the tracer was determined according to the Langendorff method. ECG gated microPET imaging (FOCUS F-120, Siemens Medical Imaging, USA) was performed, and the listmode data were sorted into dynamic sinograms corresponding to the diastolic phase of the heart cycle. After reorientation of the data time activity curves (TACs) were derived for the left ventricular cavity and myocardium, as well as tracer uptake polar maps two minutes p.i.. Rats were measured under MMF anesthesia, either during rest (n = 6) or during adenosine induced stress conditions (n = 6). Tracer retention two minutes p.i. was defined as tracer uptake divided through the integral under the input function. Results: The biodistribution of F-18 BMS-747158 – 02 is favorable for cardiac imaging: high myocardial uptake (3.1 %ID/g) combines with low uptake in lung and liver (0.3 %ID/g and 1.0 %ID/g, respectively, 10 minutes p.i. (n = 3)). The myocardial uptake is homogeneous (the average means equal 77.4 ± 6.0 % and 77.8 ± 7.8 % of the maximum uptake for the rest and stress groups, respectively). The tracer shows a high and flow independent myocardial first pass extraction fraction, averaging 0.94 ± 0.04 (3 flow velocities, n &gt;= 3 per group). Adenosine infusion (140 μg/kg/min) leads to a significant increase in myocardial tracer retention (1.68 ± 0.23 sec −1 to 3.21 ± 0.92 sec −1 ; P = 0.03). Conclusions: F-18 labeled BMS-747158 – 02 shows high extraction combined with excellent imaging characteristics in this first preclinical study of its applicability as a PET MPI agent.
977P Interim results of phase I dose escalation study of YBL-006: A novel anti-PD-1 monoclonal antibody in advanced solid tumors
Authors: K-W. Lee, J. Park, D-Y. Oh, S.H. Kim, D. Sabanathan, T.M. Kim, M. Kim, J. Yoon, H. Lee, S. Park, K. Paeng, C-Y. Ock
Journal: Annals of Oncology (2021)
LBA60 Prospective data of &gt;20,000 hospitalised patients with cancer and COVID-19 derived from the International Severe Acute Respiratory and emerging Infections Consortium WHO Coronavirus Clinical Characterisation Consortium: CCP-CANCER UK
Authors: C. Palmieri, L. Turtle, T. Drake, E. Harrison, A. Docherty, B. Greenhalf, P. Openshaw, J.K. Baillie, M.M.G. Semple
Journal: Annals of Oncology (2021)
Why don't cockatoos have war songs?
Authors: Cody Moser, Jordan Ackerman, Alex Dayer, Shannon Proksch, Paul E. Smaldino
Journal: Behavioral and Brain Sciences (2021)

Abstract We suggest that the accounts offered by the target articles could be strengthened by acknowledging the role of group selection and cultural niche construction in shaping the evolutionary trajectory of human music. We argue that group level traits and highly variable cultural niches can explain the diversity of human song, but the target articles' accounts are insufficient to explain such diversity.
COVID-19 Incidence and Mortality in Federal and State Prisons Compared With the US Population, April 5, 2020, to April 3, 2021
Authors: Neal Marquez, Julie A. Ward, Kalind Parish, Brendan Saloner, Sharon Dolovich
Journal: JAMA (2021)

Brendan Saloner, PhD; Kalind Parish, MA; Julie A. Ward, MN, RN; Grace DiLaura, JD; Sharon Dolovich, JD, PhD
Insights into the anticancer mechanisms of interleukin-15 from engineered cytokine therapies
Authors: Zachary J. Bernstein, Jamie B. Spangler
Journal: Journal of Clinical Investigation (2021)

Innovative approaches in the field of cytokine engineering are revolutionizing the cancer therapeutic landscape. The IL-15 cytokine is particularly enticing as a cancer immunotherapy due to its natural propensity for stimulating the proliferation and activation of NK and CD8+ T cells. In a recent IL-15 engineering approach, the cytokine was conjugated to polyethylene glycol, and the resulting molecule (NKTR-255) exhibited potent antitumor activities. In this issue of the JCI, Robinson et al. mechanistically explored NKTR-255 and compared its immune profile to that of the unconjugated IL-15 cytokine. The authors found that NKTR-255 employs distinct activities on NK compared with CD8+ T cells. NKTR-255 signaling also showed less dependence on the expression of the IL-15 receptor-α (IL-15Rα) chain compared with unconjugated IL-15. Collectively, these findings will advance IL-15-based clinical therapies and, more generally, benefit the field of cancer immunotherapy.