tbuckley/cabot-search huggingface dataset:
Imposter syndrome: a degree of doubt is essential
Authors: Paula Salmons
Journal: BMJ (2021)

<h3>Introduction</h3> Corporate governance, through the involvement of employees and the dynamics that it can produce, is an essential issue for efficiency and for safeguarding workers’ health. Many studies have shown that individual autonomy is a determining factor for occupational health. Employees must have individual and collective leeway in organising their work, not only applying procedures that have been defined by others but being able to show their creativity and influence their work environment. In this aim, organisational design should provide the opportunity to influence management modes, distribution of power, individual participation in the design processes. The concept of subsidiarity can help to achieve these goals. <h3>Methods</h3> From an ergonomic intervention in an insurance company about the organisation of a call centre, we can see what are the conditions to build an organisation aiming at subsidiarity, both as a target and as a process for the management of change. <h3>Results</h3> Contrary to the idea of a predetermined definition of all the decisions that can be taken at every level of the hierarchy, efficiency consists in constantly adapting the level of decision-making to the problem being dealt with. This requires constructing an organisation which is sensitive to details of events, which can be always adjusting the levels at which matters are dealt with. However, this swing from one decision level to another is only possible if the organisation and the people within it are well prepared beforehand. <h3>Conclusion</h3> The concept of subsidiarity constitutes an ethical point of reference for dealing with questions of organisational design and corporate governance. It favours decision-making at the lowest appropriate level by following three organising principles: the competency principle, the assistance principle, and the substitution principle. The way we build the interventions must be in line with this vision. It is both a matter of efficiency and a dynamic for healthy organisations.
Abstract 1076: Hormonal regulation of SEMA7A promotes therapeutic resistance in ER+ breast cancer
Authors: Lyndsey S. Crump, Garhett L. Wyatt, Taylor R. Rutherford, Jennifer K. Richer, Weston W. Porter, Traci R. Lyons
Journal: Cancer Research (2021)

Abstract Background: The majority of all breast cancers (BC) are estrogen receptor positive (ER+). While ER-targeting endocrine therapies have improved patient survival, many tumors become drug resistant and recur within 20 years. Thus, novel targets are needed to treat recurrent ER+BC. Previous reports have described tumor-promotional effects of Semaphorin 7A (SEMA7A) in ER- disease; however, the role of SEMA7A in ER+ disease is not well-characterized. Hypothesis: SEMA7A promotes cell survival and drug resistance in ER+ BC. Methods: We measured expression of SEMA7A in drug resistant cells via immunoblotting. We then overexpressed SEMA7A and used ER-targeting drugs (fulvestrant and tamoxifen) to test how SEMA7A-expressing cells respond to endocrine therapy. In vitro, we utilized cell proliferation and survival assays. In vivo, we implanted ER+ BC cells, then treated the animals with fulvestrant to assess how SEMA7A affects primary tumor volume and metastasis. We also measured markers of “stemness” and multi-drug resistance via flow cytometry. Results: We found that SEMA7A expression correlated with decreased relapse free survival in patients who received endocrine therapy for ER+BC (Kmplotter; p=0.042). We also observe that SEMA7A can be hormonally regulated in ER+BC, but expression did not consistently decrease with endocrine therapy. Instead, long term estrogen deprivation and ER-targeting treatments increased SEMA7A expression, likely through signaling via other hormone receptors such as the androgen receptor, which also increases with long term estrogen deprivation. Additionally, overexpression of SEMA7A promoted in vitro growth and survival of ER+ cells during estrogen-deprivation, tamoxifen, or fulvestrant treatments. In vivo, SEMA7A promoted fulvestrant resistance in the primary tumor and also induced lung metastases. Finally, we identified pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors. Conclusion: These studies show that SEMA7A can promote drug resistance in ER+ BC. We suggest that targeting pro-survival signaling may prove efficacious for treating SEMA7A+ tumors, which are less likely be resistant to endocrine therapies. Citation Format: Lyndsey S. Crump, Garhett L. Wyatt, Taylor R. Rutherford, Jennifer K. Richer, Weston W. Porter, Traci R. Lyons. Hormonal regulation of SEMA7A promotes therapeutic resistance in ER+ 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 1076.
Abstract 922: End-to-end discovery to support the development of safe and efficacious engineered cell therapies
Authors: Katherine Vousden, Sanne Holt, Sophie Vermond, Monique Hazenoot, Sarah Ives, Sawsan Youssef, Jake Glanville
Journal: Cancer Research (2021)

Abstract The global market for cell and gene therapies, including T-cell/Natural Killer cell chimeric antigen receptors (CAR-T/NK), is continuing to grow rapidly - with many clinical success stories for B-cell malignancies in particular. However, the path to clinical success has not been smooth - with early reports of organ damage and even deaths following CAR-T therapy highlighting that there are significant risks involved in their development, and a clear requirement to understand and mitigate for the underlying mechanisms that result in unwanted toxicities. Off-target binding and tonic signalling are indicated in many pre-clinical and clinical cell therapy failures, and it is becoming increasingly apparent that CAR design - particularly the selection of the tumor targeting moiety with exquisite specificity, desirable biophysical attributes and appropriate affinity - is key to developing a successful therapy. Distributed Bio's scFv and VHH phage-display libraries (SuperHuman 2.0 and Tungsten) have been designed to be biophysically stable and non-immunogenic. Their size and clonal diversity, coupled with the use of streamlined work-flows, enable the rapid identification of large panels of VH CDR3 sequence-unique binders which can then be assessed for CAR suitability by exploiting the integrated approach offered by DBio's successful partnership with Charles River. Panels of CAR constructs, covering the diversity of sequences and affinities related to the scFv/VHH domains isolated, can be triaged through Charles River efficacy and safety work-streams to identify the best therapeutic candidates. For example, co-culture experiments with target-expressing carcinoma cell lines and non-target expressing cell lines can be utilized to investigate and compare activity, specificity and potency of the various CAR constructs. Ultimately, combining Distributed Bio discovery with Charles River downstream characterization enables identification of the best lead candidate - balancing efficacy and safety of your CAR-T therapy - for optimal therapeutic outcome. Citation Format: Katherine Vousden, Sanne Holt, Sophie Vermond, Monique Hazenoot, Sarah Ives, Sawsan Youssef, Jake Glanville. End-to-end discovery to support the development of safe and efficacious engineered cell therapies [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 922.
Abstract 2069: Targeting the DNA damage response in combination with high Z metal nanoparticle radiosensitizers in glioblastoma
Authors: Brianna Kerr
Journal: Cancer Research (2021)

Abstract Introduction: Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis of approximately 11-15 months following standard-of-care treatments. There is a critical need for the development of clinical unmet need and a need for novel therapies in GBM. Combining novel drugs with radiotherapy has clear potential to considerably improve patient outcomes. Metal nanoparticles (NPs) and inhibitors of the DNA damage response (DDRIs) have been successfully translated to the clinical setting to benefit patients. In this study, we aimed to evaluate a novel multi-modal treatment in GBM by combining radiotherapy with metal NPs and DDRIs. Materials and methods: GBM cell models (U87 &amp; U251) were screened with different NP formulations and sizes, including gadolinium-, iron- and gold-based NPs, to determine the most effective NP. Cells were transiently exposed to NPs for 1 or 24 hr prior to irradiation by x-rays and cell survival determined. IC50 values were determined for various DDRIs which specifically target PARP, ATR, ATM and DNA-PKcs. Clonogenic cell survival assays were conducted and cells treated with NP and DDRI combinations either 1 or 24 hr prior to irradiation to define the optimum schedule for drugging. Results and conclusions: We have demonstrated the radiosensitizing potential of Activation and Guidance of Irradiation by X-ray (AGuIX), a gadolinium-based NP, at low-moderate concentrations with the highest concentration tested (2mM) showing the greatest efficacy. A promising lack of cytotoxicity on both GBM cell models was observed. In contrast to AGuIX, U87 and U251 cell survival responses indicated a lack of dose dependency when exposed to varying concentrations of Superparamagnetic Iron Oxide Nanoparticles (SPIONs). Both cell models exhibited differential radiotherapy responses when exposed to ID10 and ID11, gold-based NPs with varying PEG chain lengths. Combination treatment with AGuIX and Olaparib resulted in differential efficacy between cell lines. A non-significant difference in cell survival was observed between differing treatment scheduling. Future work will explore several variations of NP and DDRI treatments in combination with irradiation by x-rays on GBM cell models. The future implications of this research are GBM patients would receive combination therapies tailored to the specific DNA mutations in their tumor. Citation Format: Brianna Kerr. Targeting the DNA damage response in combination with high Z metal nanoparticle radiosensitizers in glioblastoma [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 2069.
SARS-CoV-2 B.1.617.2 (Delta) Variant COVID-19 Outbreak Associated with a Gymnastics Facility — Oklahoma, April–May 2021
Authors: Kendra Dougherty, Mike Mannell, Ozair Naqvi, Dakota Matson, Jolianne Stone
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

The B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, was identified in India in late 2020 and has subsequently been detected in approximately 60 countries (1). The B.1.617.2 variant has a potentially higher rate of transmission than other variants (2). During May 12-18, 2021, the Oklahoma State Department of Health (OSDH) Acute Disease Service (ADS) was notified by the OSDH Public Health Laboratory (PHL) of 21 SARS-CoV-2 B.1.617.2 specimens temporally and geographically clustered in central Oklahoma. Public health surveillance data indicated that these cases were associated with a local gymnastics facility (facility A). OSDH ADS and local health department staff members reinterviewed persons with B.1.617.2 variant-positive laboratory results and conducted contact tracing. Forty-seven COVID-19 cases (age range = 5-58 years), including 21 laboratory-confirmed B.1.617.2 variant and 26 epidemiologically linked cases, were associated with this outbreak during April 15-May 3, 2021. Cases occurred among 10 of 16 gymnast cohorts* and three staff members; secondary cases occurred in seven (33%) of 26 interviewed households with outbreak-associated cases. The overall facility and household attack rates were 20% and 53%, respectively. Forty (85%) persons with outbreak-associated COVID-19 had never received any COVID-19 vaccine doses (unvaccinated); three (6%) had received 1 dose of Moderna or Pfizer-BioNTech ≥14 days before a positive test result but had not received the second dose (partially vaccinated); four persons (9%) had received 2 doses of Moderna or Pfizer-BioNTech or a single dose of Janssen (Johnson & Johnson) vaccine ≥14 days before a positive test result (fully vaccinated). These findings suggest that the B.1.617.2 variant is highly transmissible in indoor sports settings and within households. Multicomponent prevention strategies including vaccination remain important to reduce the spread of SARS-CoV-2, including among persons participating in indoor sports† and their contacts.
Abstract 1771: SIGLEC15 humanized knock-in mice are a powerful tool to evaluate new therapies for cancer and osteoporosis
Authors: Huilin Li, Lei Zhao, Maopeng Tian, Veronika Chromikova, Zhaoxue (Luke) Yu
Journal: Cancer Research (2021)

Abstract SIGLEC15 (Sialic acid-binding immunoglobulin-like lectin 15) belongs to the Siglec family of sialic acid-binding, immunoglobulin-like proteins. SIGLEC15 is an effective immunosuppressive molecule which is highly expressed on M2 macrophages but can be upregulated in many human cancers. The SIGLEC15 signaling pathway is non-redundant to the PD-L1 pathway in cancer, and the surface expression of SIGLEC15 is generally non-overlapping with PD-L1 expression on tumors. SIGLEC15 engages a putative responder protein expressed on the surface of effector cells, such as CD8 T cells, inducing suppression of anti-tumor immune responses. Blocking of SIGLEC15 amplifies anti-tumor immunity in the tumor microenvironment and inhibits tumor growth. This opens a road for anti-SIGLEC15 antibody therapeutics which may provide a solution for patients with SIGLEC15-positive and PD-L1-negative tumors, a patient population less likely to respond to a PD-1/PD-L1 directed therapy. Biocytogen has generated a humanized SIGLEC15 mouse model to address the need for in vitro functional validation and in vivo efficacy evaluation of SIGLEC15-targeting strategies. In these mice, genomic DNA spanning exons 2~4 of mouse Siglec15 gene encoding the extracellular domain, was replaced by its human counterpart. Following the humanization procedure, human SIGLEC15 could be detected on bone marrow derived macrophages (BMDM). Basal leukocyte subpopulations, including T/B/NK cells, DC, granulocytes, and monocytes/macrophages, were similar between humanized and wild-type mice. In addition, Biocytogen has generated a humanized MC38 cell line, in which the mouse Siglec15 gene was replaced with the full-length human coding sequence. The successful humanization of M38 was confirmed by RT-PCR and flow cytometry. Using the hMC38 tumor model, we showed robust efficacy of the anti-SIGLEC15 antibodies in inhibiting tumor growth in vivo. Combined SIGLEC15 and PD-1/PD-L1 blockade showed greater tumor inhibition than monotherapies. In summary, SIGLEC15 humanized mice can be employed for in vivo efficacy evaluation of anti-SIGLEC15 antibodies in immune normalization approaches for cancer treatment. Besides the tumor models (B16F10 and other tumors underway), we are also actively exploring the feasibility of the SIGLEC15 humanized mice as a pre-clinical model for osteoporosis in a light of recent discovery of SIGLEC15's role in osteoclast differentiation. Citation Format: Huilin Li, Lei Zhao, Maopeng Tian, Veronika Chromikova, Zhaoxue (Luke) Yu. SIGLEC15 humanized knock-in mice are a powerful tool to evaluate new therapies for cancer and osteoporosis [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 1771.
EEG findings in CAR T-cell-associated neurotoxicity: Clinical and radiological correlations
Authors: Isabelle Beuchat, Husain H Danish, Daniel B Rubin, Caron Jacobson, Matthew Robertson, Henrikas Vaitkevicius, Jong Woo Lee
Journal: Neuro-Oncology (2021)

While EEG is frequently reported as abnormal after chimeric antigen receptor (CAR) T-cell therapy, its clinical significance remains unclear. We aim to systematically describe EEG features in a large single-center cohort and correlate them with clinical and radiological findings.We retrospectively identified patients undergoing CAR T-cell therapy who had continuous EEG. Neurotoxicity grades, detailed neurological symptoms, and brain MRI or FDG-PET were obtained. Correlation between clinical and radiological findings and EEG features was assessed.In 81 patients with median neurotoxicity grade 3 (IQR 2-3), diffuse EEG background slowing was the most common finding and correlated with neurotoxicity severity (P <.001). A total of 42 patients had rhythmic or periodic patterns, 16 of them within the ictal-interictal-continuum (IIC), 5 with clinical seizures, and 3 with only electrographic seizures. Focal EEG abnormalities, consisting of lateralized periodic discharges (LPD, n = 1), lateralized rhythmic delta activity (LRDA, n = 6), or focal slowing (n = 19), were found in 22 patients. All patients with LRDA, LPD, and 10/19 patients with focal slowing had focal clinical symptoms concordant with these EEG abnormalities. In addition, these focal EEG changes are often correlated with PET hypometabolism or MRI hypoperfusion, in absence of a structural lesion.In adult patients experiencing neurotoxicity after CAR T-cell infusion, EEG degree of background disorganization correlated with neurotoxicity severity. IIC patterns and focal EEG abnormalities are frequent and often correlate with focal clinical symptoms and with PET-hypometabolism/MRI-hypoperfusion, without structural lesion. The etiology of these findings remains to be elucidated.
The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells
Authors: Moritz Bewarder, Maximilian Kiefer, Helene Will, Kathrin Olesch, Clara Moelle, Stephan Stilgenbauer, Konstantinos Christofyllakis, Dominic Kaddu-Mulindwa, Joerg Thomas Bittenbring, Natalie Fadle, Evi Regitz, Lea Kaschek, Markus Hoth, Frank Neumann, Klaus-Dieter Preuss, Michael Pfreundschuh, Lorenz Thurner
Journal: HemaSphere (2021)

Mantle cell lymphoma (MCL) accounts for 5%–10% of all lymphomas. The disease’s genetic hallmark is the t(11; 14)(q13; q32) translocation. In younger patients, the first-line treatment is chemoimmunotherapy followed by autologous stem cell transplantation. Upon disease progression, novel and targeted agents such as the BTK inhibitor ibrutinib, the BCL-2 inhibitor venetoclax, or the combination of both are increasingly used, but even after allogeneic stem cell transplantation or CAR T-cell therapy, MCL remains incurable for most patients. Chronic antigenic stimulation of the B-cell receptor (BCR) is thought to be essential for the pathogenesis of many B-cell lymphomas. LRPAP1 has been identified as the autoantigenic BCR target in about 1/3 of all MCLs. Thus, LRPAP1 could be used to target MCL cells, however, there is currently no optimal therapeutic format to integrate LRPAP1. We have therefore integrated LRPAP1 into a concept termed BAR, for B-cell receptor antigens for reverse targeting. A bispecific BAR body was synthesized consisting of the lymphoma-BCR binding epitope of LRPAP1 and a single chain fragment targeting CD3 or CD16 to recruit/engage T or NK cells. In addition, a BAR body consisting of an IgG1 antibody and the lymphoma-BCR binding epitope of LRPAP1 replacing the variable regions was synthesized. Both BAR bodies mediated highly specific cytotoxic effects against MCL cells in a dose-dependent manner at 1–20 µg/mL. In conclusion, LRPAP1 can substitute variable antibody regions in different formats to function in a new therapeutic approach to treat MCL.
Endophthalmitis Rate in Immediately Sequential versus Delayed Sequential Bilateral Cataract Surgery within the Intelligent Research in Sight (IRIS®) Registry Data
Authors: Megan Lacy, Timothy-Paul H Kung, Julia P Owen, Ryan T Yanagihara, Marian Blazes, Suzann Pershing, Leslie G Hyman, Russell N Van Gelder, Aaron Y Lee, Cecilia S Lee
Journal: Ophthalmology (2021)
Abstract 1244: Discovery of a novel anticancer benzopyrane derivative with an effective multitarget mechanism of action
Authors: Dana Zaher, Wafaa Ramadan, Raafat El-Awady, Hany Omar, Fatema Hersi, Vunnam Srinivasulu, Taleb Al-Tel
Journal: Cancer Research (2021)

Abstract Introduction: Cancer is a leading cause of death worldwide, as about 1 in 6 deaths is due to cancer. Despite the advances in cancer treatment, the success rate of cancer cure is very low, due to the low therapeutic index and many off target side effects of the available anticancer drugs. This highlight the urgent need for the development of novel anticancer compounds with high efficacy and wide safety margin. Methods: Phenotypic screening of a skeletally diverse library of benzopyrane yielded a unique chemotype with novel anticancer mechanism. Cell viability assays were performed against a panel of cancer cell lines followed by various assays to verify the effect of our compound on inducing apoptosis, DNA damage, cell cycle arrest. For further explore the compound's mechanism of action, a proteomic study was conducted along with western blot analysis, metabolism studies and other enzymes specific mechanistic assays. In addition, mouse tumor model was developed to assess the safety and the activity of the compound in vivo. Results: The novel compound possesses a potent anticancer effect against multiple cancer cell lines, induces apoptosis, DNA damage and perturbs the cell cycle progression. Interestingly, it inhibits the activity of essential enzymes involved in the cell's redox balance including Thioredoxin and Glutathione reductases. Moreover, it inactivates vital cancer survival pathways. Lastly, the compound safely reduces tumor proliferation in vivo. Conclusion: Due to the achieved safety profile, potency and efficacy of this novel benzopyrane derived agent as well as its unique mechanism of action, the compound is a potential candidate for further testing in preclinical and clinical settings. Keywords: Multitarget, apoptosis, DNA damage, cell cycle, thioredoxin reductase, glutathione reductase Citation Format: Dana Zaher, Wafaa Ramadan, Raafat El-Awady, Hany Omar, Fatema Hersi, Vunnam Srinivasulu, Taleb Al-Tel. Discovery of a novel anticancer benzopyrane derivative with an effective multitarget mechanism of action [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 1244.