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Breast cancer screening recommendations for transgender and gender diverse (TGD) patients have only been recently developed and many primary care practitioners (PCPs) are unaware of these specific recommendations. The aim of this study is to assess the level of familiarity and knowledge PCPs have with breast cancer screening recommendations for TGD patients. An anonymous survey was distributed to primary care physicians, primary care advanced practice practitioners, and internal medicine and family medicine residents at three academic medical systems in the United States (Mayo Clinic, University of Michigan, University of Texas – Medical Branch). Survey questions assessed the familiarity and knowledge base of TGD breast cancer screening recommendations, training and experience with TGD patients, and basic demographics of the practitioners. Of the 95 survey respondents, only 35% of respondents were aware that breast cancer screening recommendations for TGD patients existed. PCPs who had increased transgender specific health care training and direct clinical exposure to TGD patients demonstrated significantly higher levels of screening recommendation awareness. Two-thirds of respondents received TGD specific medical education during training or medical career and those who had increased transgender specific medical education or direct clinical exposure to TGD patients demonstrated significantly higher levels of screening recommendation awareness. Awareness of breast cancer screening recommendations for TGD patients is low among PCPs and varied based on the practitioner’s prior TGD education and experience. Up-to-date breast cancer screening recommendations for TGD patients should be readily available across multiple platforms, target key audiences, and integrated into transgender health educational curriculums to maximize awareness of these important recommendations.

Transgender and gender diverse (TGD) people experience health disparities, and many avoid necessary medical care because of fears of discrimination or mistreatment. Disparate care is further compounded by limited understanding of gender-affirming hormone therapy (GAHT) and gender-affirming surgery among the medical community. Specific to radiology, TGD patients report more negative imaging experiences than negative general health encounters, highlighting the need for guidance and best practices for inclusive imaging care. A patient's imaging journey provides numerous opportunities for improvement. Inclusive practice in a radiology department starts with ordering and scheduling the examination, facilitated by staff education on appropriate use of a patient's chosen name, gender identity, and pronouns. Contemporary electronic health record systems have the capacity for recording detailed sexual orientation and gender identity data, but staff must be trained to solicit and use this information. A welcoming environment can help TGD patients to feel safe during the imaging experience and may include institutional nondiscrimination policies, gender-neutral signage, and all-gender single-user dressing rooms and bathrooms. Image acquisition should be performed using trauma-informed and patient-centered care. Finally, radiologists should be aware of reporting considerations for TGD patients, such as avoiding the use of gender in reports when it is not medically relevant and using precise, respectful language for findings related to GAHT and gender-affirming surgical procedures. As a field, radiology has a range of opportunities for improving care delivery for TGD patients, and the authors summarize recommended best practices. See the invited commentary by Stowell in this issue.

Background The Nursing department within an acute general hospital wished to illuminate and build on positive local enhanced care practices. A collaborative research team was formed between academics in the linked higher education institution and nurses within the hospital to address this intent by building nurse-led research capacity, while addressing the practice derived research question. Methods A mixed methods approach was employed involving; site visits, audit of enhanced care staffing requirements, documentary and activity box analyses and use of appreciative inquiry (AI) methodology. AI is a collaborative and strengths-oriented approach supporting organisational development. It was implemented via three World Café events (www.theworldcafe.com 2021) bringing together hospital stakeholders (n = 17) with direct experience of delivering enhanced care, to consider pre-defined questions. Thematic analysis was used to analyse the resultant data. Ethical approval was obtained. Results Overall, the findings demonstrated a positive focus on implementing therapeutic enhanced care within the hospital in contrast to a more passive primarily observational orientation. The site visits facilitated shared learning. Thematic findings from the World Cafés identified positive care practices and enabled a multidisciplinary, inclusive approach, which facilitated pragmatic suggestions on how to plan for, and build on existing foundations of, enhanced care practice. Conclusion Both the study approach and outcome resulted in positive impacts. Working collaboratively supported research capacity building for hospital-based members of the research team. Using AI supported constructive and inclusive stakeholder participation in the World Cafés with a focus on good practices and ways in which they could be strengthened. One year post completion, study recommendations have led to

The inclusion and celebration of LGBTQIA+ staff in radiology and radiation oncology departments is crucial in developing a diverse and thriving workplace. Despite the substantial social change in Australia, LGBTQIA+ people still experience harassment and exclusion, negatively impacting their well-being and workplace productivity. We need to be proactive in creating policies that are properly implemented and translate to a safe and inclusive space for marginalised groups. In this work, we outline the role we all can play in creating inclusive environments, for both individuals and leaders working in radiology and radiation oncology. We can learn how to avoid normative assumptions about gender and sexuality, respect people's identities and speak out against witnessed discrimination or slights. Robust policies are needed to protect LGBTQIA+ members from discrimination and provide equal access across other pertinent parts of work life such as leave entitlements, representation in data collection and safe bathroom access. We all deserve to feel safe and respected at work and further effort is needed to ensure this extends to LGBTQIA+ staff in the radiology and radiation oncology workforces.

Multiple myeloma (MM), a cancer of plasma cells, occurs in ~34,000 new patients every year in the USA. Although therapeutic regimens, including anti-CD38 monospecific IgG antibodies such as daratumumab and isatuximab in combination with chemotherapies, demonstrate clinical efficacy, most patients eventually develop resistance. Several bispecific (CD38xCD3) or trispecific (CD38xCD3xCD28) T cell engager (TCE) antibody therapies are currently in development to improve upon the efficacy of CD38 targeted therapies by leveraging T cell dependent cellular cytotoxicity (TDCC) of MM cells. However, CD38 is also expressed on some normal hematopoietic cells which could potentially lead to undesired pharmacological activity such as depleting CD38+ immune cells, including activated cytotoxic T cells (i.e., fratricide). IGM-2644 is a novel, pentameric IgM antibody engineered to have ten CD38 binding sites, and an anti-CD3ε single chain Fv domain fused to a joining chain to engage CD3 on T cells, and retains the potential for complement-dependent cytotoxicity (CDC). Here we report the functional characterization of IGM-2644 using in vitro, ex vivo and in vivo anti-tumor efficacy studies with a safety evaluation of this novel IgM TCE. In vitro, IGM-2644 demonstrated significantly improved CDC activity in comparison with daratumumab and isatuximab, with >30-fold increased potency on CD38+ MM and lymphoma cell lines. IGM-2644 induced TDCC similar to a bispecific CD38xCD3 IgG on low CD38 expressing cell lines resistant to daratumumab, while demonstrating significantly lower levels of cytokine release than the bispecific IgG. In ex vivo colony forming unit (CFU) assays, IGM-2644 was able to reduce MM CFUs using primary MM patient bone marrow samples containing autologous T cells and myeloma cells, while no effect was observed on erythroid, granulocyte and macrophage CFUs in normal bone marrow samples.​ IGM-2644 dose dependently inhibited tumor growth in humanized xenograft models of CD38+ NCI-H929 (myeloma) and Raji (lymphoma). Importantly, IGM-2644 also demonstrated significantly reduced T cell fratricide compared to bispecific IgGs both ex vivo and in vivo. Significantly reduced activity of IGM-2644 on normal CD38+ innate immune cells was observed in ex vivo studies. CD38 expression has also been reported on human RBCs and platelets. However, minimal IGM-2644 binding was observed and at levels lower than daratumumab. In summary, IGM-2644 is a novel, potent, bispecific IgM TCE that has both CDC and TDCC mechanisms of cytotoxicity with the potential to be active in daratumumab resistant tumors. The balance of potent TDCC and CDC cytotoxic activity, along with an improved preclinical safety profile compared to other CD38xCD3 bispecific IgG TCEs, supports the clinical development of IGM-2644 in MM. Citation Format: Keyu Li, Rui Yun, Min Chai, Poonam Yakkundi, Rodnie Rosete, Gene Li, Liqin Liu, Mandy Li, Daniel Santos, Kevin C. Hart, Dean Ng, Paul R. Hinton, Umesh Muchhal, Thomas Manley, Maya F. Kotturi, Stephen F. Carroll, Angus M. Sinclair, Bruce A. Keyt. Novel CD38xCD3 bispecific IgM T cell engager, IGM-2644, potently kills multiple myeloma cells though complement and T cell dependent mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2959.

Imvotamab (IGM-2323) is an engineered high-affinity, high-avidity bispecific anti-CD20 IgM antibody T cell engager (TCE) that is currently being studied as monotherapy in a Phase 1/2 clinical trial for relapsed/refractory non-Hodgkin’s lymphoma (NHL) (NCT04082936). Imvotamab offers a novel treatment strategy in NHL by depleting CD20-expressing tumor cells through multiple mechanisms, including the recruitment of T cells to kill tumor cells through T cell dependent cellular cytotoxicity, complement-dependent cytotoxicity, and enhanced immune modulation via IFNγ-dominant cytokine stimulation. We evaluated the activity of a surrogate cynomolgus monkey cross-reactive CD20xCD3 IgM bispecific TCE, IGM-2324, in depleting CD20-expressing B cells in peripheral blood and lymphoid tissues of cynomolgus monkeys in vivo. We hypothesized that the high affinity and valency of IGM-2324 would enable potent B cell killing in blood and tissues even when B cells express low levels of CD20. Cynomolgus monkeys were administered vehicle or IGM-2324 at 5 mg/kg or 25 mg/kg through intravenous infusion twice weekly for a total of four doses on days 1, 4, 7, and 10. B cell depletion in peripheral blood was assessed by measuring the frequency of CD19+ B cells through flow cytometry. Administration of IGM-2324 at 5 and 25 mg/kg resulted in a nearly complete depletion in peripheral CD19+ B cells at 8 hours post the 1st dose through 24 hours post the last dose on day 11. Depletion of tissue-resident B cells was evaluated in the spleen, mesenteric lymph node (MLN) and bone marrow (BM) of monkeys at 24 hours post the last dose of vehicle or IGM-2324 on day 11. Immunohistochemistry studies were conducted on the formalin-fixed paraffin-embedded lymphoid tissues by staining for CD19 and CD20 expression. The number and intensity of CD19 or CD20 positive B cells were determined by quantitative imaging analysis. Compared to vehicle-treated animals, significant dose-dependent reductions in both CD19 and CD20-expressing B cells were observed in spleen, MLN and BM following treatment with 5 and 25 mg/kg of IGM-2324. Most importantly, IGM-2324 treatment led to the depletion of not only high and moderate tissue-resident CD20-expressing B cells, but also B cells that expressed low levels of CD20. Our preclinical data indicate that a CD20xCD3 IgM bispecific TCE can penetrate tissues and mediate direct killing of CD20-expressing target cells. B cell depletion in the periphery and tumors of relapsed/refractory NHL patients is currently being evaluated as biomarker of pharmacodynamic activity and/or efficacy for imvotamab in a Phase 1/2 clinical study. Citation Format: Miho Oyasu, Angus M. Sinclair, Haben Ghermazien, Genevive Hernandez, Thomas Manley, Maya K. Leabman, Stephen F. Carroll, Bruce A. Keyt, Maya F. Kotturi. Depletion of tissue-resident B cells by a CD20xCD3 IgM bispecific T cell engager in cynomolgus monkeys demonstrates effective tissue penetration and potent target cell killing. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4120.

Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage that is resistant to vascularization and endochondral ossification. During skeletal development articular cartilage also functions as a surface growth plate, which postnatally is replaced by a more spatially complex bone-cartilage interface. Motivated by this developmental process, the hypothesis of this study is that bi-phasic, fibre-reinforced cartilaginous templates can regenerate both the articular cartilage and subchondral bone within osteochondral defects created in caprine joints. To engineer mechanically competent implants, we first compared a range of 3D printed fibre networks (PCL, PLA and PLGA) for their capacity to mechanically reinforce alginate hydrogels whilst simultaneously supporting mesenchymal stem cell (MSC) chondrogenesis in vitro. These mechanically reinforced, MSC-laden alginate hydrogels were then used to engineer the endochondral bone forming phase of bi-phasic osteochondral constructs, with the overlying chondral phase consisting of cartilage tissue engineered using a co-culture of infrapatellar fat pad derived stem/stromal cells (FPSCs) and chondrocytes. Following chondrogenic priming and subcutaneous implantation in nude mice, these bi-phasic cartilaginous constructs were found to support the development of vascularised endochondral bone overlaid by phenotypically stable cartilage. These fibre-reinforced, bi-phasic cartilaginous templates were then evaluated in clinically relevant, large animal (caprine) model of osteochondral defect repair. Although the quality of repair was variable from animal-to-animal, in general more hyaline-like cartilage repair was observed after 6 months in animals treated with bi-phasic constructs compared to animals treated with commercial control scaffolds. This variability in the quality of repair points to the need for further improvements in the design of 3D bioprinted implants for joint regeneration. STATEMENT OF SIGNIFICANCE: Successful osteochondral defect repair requires regenerating the subchondral bone whilst simultaneously promoting the development of an overlying layer of articular cartilage. In this study, we hypothesised that bi-phasic, fibre-reinforced cartilaginous templates could be leveraged to regenerate both the articular cartilage and subchondral bone within osteochondral defects. To this end we used 3D printed fibre networks to mechanically reinforce engineered transient cartilage, which also contained an overlying layer of phenotypically stable cartilage engineered using a co-culture of chondrocytes and stem cells. When chondrogenically primed and implanted into caprine osteochondral defects, these fibre-reinforced bi-phasic cartilaginous grafts were shown to spatially direct tissue development during joint repair. Such developmentally inspired tissue engineering strategies, enabled by advances in biofabrication and 3D printing, could form the basis of new classes of regenerative implants in orthopaedic medicine.

The COVID-19 pandemic is now approaching 2 years old, with more than 440 million people infected and nearly six million dead worldwide, making it the most significant pandemic since the 1918 influenza pandemic. The severity and significance of SARS-CoV-2 was recognized immediately upon discovery, leading to innumerable companies and institutes designing and generating vaccines and therapeutic antibodies literally as soon as recombinant SARS-CoV-2 spike protein sequence was available. Within months of the pandemic start, several antibodies had been generated, tested, and moved into clinical trials, including Eli Lilly's bamlanivimab and etesevimab, Regeneron's mixture of imdevimab and casirivimab, Vir's sotrovimab, Celltrion's regdanvimab, and Lilly's bebtelovimab. These antibodies all have now received at least Emergency Use Authorizations (EUAs) and some have received full approval in select countries. To date, more than three dozen antibodies or antibody combinations have been forwarded into clinical trials. These antibodies to SARS-CoV-2 all target the receptor-binding domain (RBD), with some blocking the ability of the RBD to bind human ACE2, while others bind core regions of the RBD to modulate spike stability or ability to fuse to host cell membranes. While these antibodies were being discovered and developed, new variants of SARS-CoV-2 have cropped up in real time, altering the antibody landscape on a moving basis. Over the past year, the search has widened to find antibodies capable of neutralizing the wide array of variants that have arisen, including Alpha, Beta, Gamma, Delta, and Omicron. The recent rise and dominance of the Omicron family of variants, including the rather disparate BA.1 and BA.2 variants, demonstrate the need to continue to find new approaches to neutralize the rapidly evolving SARS-CoV-2 virus. This review highlights both convalescent plasma- and polyclonal antibody-based approaches as well as the top approximately 50 antibodies to SARS-CoV-2, their epitopes, their ability to bind to SARS-CoV-2 variants, and how they are delivered. New approaches to antibody constructs, including single domain antibodies, bispecific antibodies, IgA- and IgM-based antibodies, and modified ACE2-Fc fusion proteins, are also described. Finally, antibodies being developed for palliative care of COVID-19 disease, including the ramifications of cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS), are described.

Mesenchymal stem/stromal cells (MSCs) represent a promising cell type for treating damaged synovial joints. The therapeutic potential of MSCs will be facilitated by the engineering of biomaterial environments capable of directing their fate. Here the interplay between matrix elasticity and cell morphology in regulating the chondrogenic differentiation of MSCs when seeded onto or encapsulated within hydrogels made of interpenetrating networks (IPN) of alginate and collagen type I is explored. This IPN system enables the independent control of substrate stiffness (in 2D and in 3D) and cell morphology (3D only). The expression of chondrogenic markers SOX9, ACAN, and COL2 increases when MSCs are cultured onto the soft substrate, which correlates with increased SMAD2/3 nuclear localization, enhanced MSCs condensation, and the formation of larger cellular aggregates. The encapsulation of spread MSCs within a soft IPN increases the expression of cartilage-specific genes, which is linked to cellular condensation and nuclear SMAD2/3 localization. Surprisingly, cells forced to adopt a more rounded morphology within the same soft IPNs expressed higher levels of the osteogenic markers RUNX2 and COL1. The insight provided by this study suggests that a mechanobiology informed approach to biomaterial development will be integral to the development of successful cartilage tissue engineering strategies.

We investigate the topological classification of the subgap bands induced in a two-dimensional superconductor by a densely packed chain of magnetic moments with ferromagnetic or spiral alignments. The wave functions for these bands are composites of Yu-Shiba-Rusinov-type states and magnetic scattering states and have a significant spatial extension away from the magnetic moments. We show that this spatial structure prohibits a straightforward extraction of a Hamiltonian useful for the topological classification. To address the latter correctly we construct a family of spatially varying topological Hamiltonians for the subgap bands adapted for the broken translational symmetry caused by the chain. The spatial dependence in particular captures the transition to the topologically trivial bulk phase when moving away from the chain by showing how this, necessarily discontinuous, transition can be understood from an alignment of zeros with poles of Green's functions. Through the latter the topological Hamiltonians reflect a characteristic found otherwise primarily in strongly interacting systems., Comment: 15 pages, 8 figures. This is Part II of manuscript at arXiv:1709.06093 and covers topological classification

The Los Angeles (LA) classification is the most accurate means of assessing esophageal injury from caustic gastric acid with focused and greater concentrations in areas of erosive disease.1 However, data from animal models and patients have proposed that an initial diffuse inflammatory pathway contributes to injury in gastroesophageal reflux disease (GERD) mediated by interleukin (IL) 8, IL1β,2,3 and hypoxia-inducible factors.4,5 These observations demonstrate a lymphocyte predominant inflammatory process over course of 1-2 weeks associated with basal zone hyperplasia and dilation of intercellular spaces.6 In cultured human esophageal epithelial cells and patients, it is further suggested that acid causes this chronic inflammatory reaction.

Biological scaffolds generated from tissue-derived extracellular matrix (ECM) are commonly used clinically for soft tissue regeneration. Such biomaterials can enhance tissue-specific differentiation of adult stem cells, suggesting that structuring different ECMs into multi-layered scaffolds can form the basis of new strategies for regenerating damaged interfacial tissues such as the osteochondral unit. In this study, mass spectrometry is used to demonstrate that growth plate (GP) and articular cartilage (AC) ECMs contain a unique array of regulatory proteins that may be particularly suited to bone and cartilage repair respectively. Applying a novel iterative freeze-drying method, porous bi-phasic scaffolds composed of GP ECM overlaid by AC ECM are fabricated, which are capable of spatially directing stem cell differentiation in vitro, promoting the development of graded tissues transitioning from calcified cartilage to hyaline-like cartilage. Evaluating repair 12-months post-implantation into critically-sized caprine osteochondral defects reveals that these scaffolds promote regeneration in a manner distinct to commercial control-scaffolds. The GP layer supports endochondral bone formation, while the AC layer stimulates the formation of an overlying layer of hyaline cartilage with a collagen fiber architecture better recapitulating the native tissue. These findings support the use of a bi-layered, tissue-specific ECM derived scaffolds for regenerating spatially complex musculoskeletal tissues.

Medical imaging plays an integral role in the preoperative evaluation and postoperative management of transgender and gender diverse (TGD) patients who pursue gender-affirming surgery. Radiology department encounters can be a source of anxiety for patients of any demographic, including TGD patients. Although most imaging modalities are considered “non-invasive”, certain imaging procedures and other aspects of the radiology encounter could be considered quite invasive to the TGD patient. The TGD patient may be worried that the imaging examination will have to address anatomy that they feel does not align with their gender identity, or reveal some abnormality or disheartening complication of their surgery. Simultaneously, the patient must also navigate potentially uncomfortable interactions with other patients in department waiting rooms, restrooms, and changing facilities as well as with radiology staff. As the referral source to imaging facilities, providers should advocate on behalf of their TGD patients. Referring providers should work with imaging facilities to ensure their patients will receive inclusive and affirming care and not be subject to discomfort on the part of gender identity or expression. Proactive and regular communication among radiology facilities, patients, and referring providers will ensure appropriate and sensitive care for this vulnerable population. A positive imaging experience can improve patient outcomes and the relationship between healthcare providers and the TGD community they serve.

Background: No evidence currently exists characterising global outcomes following major cancer surgery, including esophageal cancer. Therefore, this study aimed to characterise impact of high income countries (HIC) versus low and middle income countries (LMIC) on the outcomes following esophagectomy for esophageal cancer. Method: This international multi-center prospective study across 137 hospitals in 41 countries included patients who underwent an esophagectomy for esophageal cancer, with 90-day follow-up. The main explanatory variable was country income, defined according to the World Bank Data classification. The primary outcome was 90-day postoperative mortality, and secondary outcomes were composite leaks (anastomotic leak or conduit necrosis) and major complications (Clavien-Dindo Grade III-V). Multivariable generalized estimating equation models were used to produce adjusted odds ratios (ORs) and 95% confidence intervals (CI95%). Results: Between April 2018 to December 2018, 2247 patients were included. Patients from HIC were more significantly older, with higher ASA grade, and more advanced tumors. Patients from LMIC had almost three-fold increase in 90-day mortality, compared to HIC (9.4% vs 3.7%, p < 0.001). On adjusted analysis, LMIC were independently associated with higher 90-day mortality (OR: 2.31, CI95%: 1.17-4.55, p = 0.015). However, LMIC were not independently associated with higher rates of anastomotic leaks (OR: 1.06, CI95%: 0.57-1.99, p = 0.9) or major complications (OR: 0.85, CI95%: 0.54-1.32, p = 0.5), compared to HIC. Conclusion: Resections in LMIC were independently associated with higher 90-day postoperative mortality, likely reflecting a failure to rescue of these patients following esophagectomy, despite similar composite anastomotic leaks and major complication rates to HIC. These findings warrant further research, to identify potential issues and solutions to improve global outcomes following esophagectomy for cancer. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Background The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. Methods Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. Results Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). Conclusion Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on perioperative outcomes in the international multicentre Oesophago-Gastric Anastomosis Audit (OGAA). Analysis of 2232 oesophagectomies has shown that trainee involvement did not negatively impact perioperative outcomes.

Rituximab-containing treatment regimens are the standard of care for patients with non-Hodgkin’s lymphoma (NHL). However, the majority of patients ultimately experience disease relapse or progression indicating resistance to rituximab therapy. IGM-2323 is an engineered high-affinity, high-avidity anti-CD20 pentameric IgM antibody with an anti-CD3 scFv fused to the joining chain. IGM-2323 offers a novel treatment strategy in NHL through two mechanisms: 1) the recruitment of T cells to kill CD20-expressing tumor cells through T cell dependent cellular cytotoxicity (TDCC) and, 2) complement-dependent cytotoxicity (CDC). We evaluated the activity of IGM-2323 in the presence of rituximab since rituximab can persist in patients after treatment discontinuation, and it can bind to an overlapping epitope on CD20 as IGM-2323. We hypothesized that the high valency of IGM-2323 could displace rituximab, thus enabling potent B cell killing by IGM-2323 even in the presence of high concentrations of rituximab. The affinity of IGM-2323 and its corresponding bivalent anti-CD20 IgG antibody to recombinant human CD20 protein were measured by surface plasmon resonance. IGM-2323 bound to human CD20 with an apparent 300-fold higher binding affinity (KD) and ~100-fold slower off-rate (kdis) than the bivalent anti-CD20 IgG. Human B cell lines with a range of CD20 expression levels, including a CD20-low rituximab-resistant Ramos cell variant, were pre-treated with escalating concentrations of rituximab, and subsequently evaluated in vitro for cell binding, TDCC, and CDC by IGM-2323. At high concentrations of rituximab, which correspond to reported peak serum concentrations (Cmax) found in rituximab-treated patients, IGM-2323 displaced the binding of rituximab on human B cell lines. In contrast, binding of a bispecific CD20xCD3 IgG was severely inhibited by the Cmax of rituximab. In TDCC assays with healthy donor effector T cells, pre-treatment with high concentrations of rituximab only modestly inhibited IGM-2323 activity. Furthermore, only a minor impact to the maximum killing activity (Emax) of IGM-2323 was observed at the Cmax of rituximab. In contrast, rituximab pre-treatment resulted in a distinctly lower Emax of a bispecific CD20xCD3 IgG. Live cell imaging of CDC kinetics was utilized to quantify the extent of CDC by IGM-2323 with or without rituximab. Pre-treatment with rituximab enhanced CDC of IGM-2323 compared to single agent activity. Our preclinical data indicate that IGM-2323 maintains activity in the presence of rituximab. IGM-2323 is currently being studied in a phase 1 clinical trial in relapsed/refractory NHL, where it has been generally well tolerated, with both complete and partial responses observed (NCT04082936). Clinical studies will continue to evaluate these findings, including the treatment of patients with circulating serum levels of rituximab. Citation Format: Kevin C. Hart, Kathryn Logronio, Mandy Li, Poonam Yakkundi, Marigold Manlusoc, Keyu Li, Paul R. Hinton, Dean Ng, Maya K. Leabman, Genevive Hernandez, Thomas Manley, Angus M. Sinclair, Stephen F. Carroll, Bruce A. Keyt, Maya F. Kotturi. High valency of IGM-2323, a CD20xCD3 IgM bispecific T cell engager, displaces rituximab binding and induces potent B lymphoma cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4179.

Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) or 12 (hexamer) antigen binding domains consisting of paired µ heavy chains with four constant domains, each with a single variable domain, paired with a corresponding light chain. Although the antigen binding affinities of natural IgM antibodies are typically lower than IgG, their polyvalency allows for high avidity binding and efficient engagement of complement to induce complement-dependent cell lysis. The high avidity of IgM antibodies renders them particularly efficient at binding antigens present at low levels, and non-protein antigens, for example, carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a joining (J) chain that stabilizes the pentameric structure and enables binding to several receptors. One such receptor, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lung and gastrointestinal tract. Several naturally occurring IgM antibodies have been explored as therapeutics in clinical trials, and a new class of molecules, engineered IgM antibodies with enhanced binding and/or additional functional properties are being evaluated in humans. Here, we review the considerable progress that has been made regarding the understanding of biology, structure, function, manufacturing, and therapeutic potential of IgM antibodies since their discovery more than 80 years ago.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Metastasis is the major cause of TNBC mortality. Angiogenesis facilitates TNBC metastases. Many TNBCs also form vascular channels lined by tumor cells rather than endothelial cells, known as ‘vasculogenic mimicry’ (VM). VM has been linked to metastatic TNBC behavior and resistance to anti-angiogenic agents. Epidermal growth factor receptor (EGFR) is frequently expressed on TNBC, but anti-EGFR antibodies have limited efficacy. We synthesized an anti-EGFR antibody–endostatin fusion protein, αEGFR IgG1-huEndo-P125A (αEGFR-E-P125A), designed to deliver a mutant endostatin, huEndo-P125A (E-P125A), to EGFR expressing tumors, and tested its effects on angiogenesis, TNBC VM, and motility in vitro, and on the growth and metastasis of two independent human TNBC xenograft models in vivo. αEGFR-E-P125A completely inhibited the ability of human umbilical vein endothelial cells to form capillary-like structures (CLS) and of TNBC cells to engage in VM and form tubes in vitro. αEGFR-E-P125A treatment reduced endothelial and TNBC motility in vitro more effectively than E-P125A or cetuximab, delivered alone or in combination. Treatment of TNBC with αEGFR-E-P125A was associated with a reduction in cytoplasmic and nuclear β-catenin and reduced phosphorylation of vimentin. αEGFR-E-P125A treatment of TNBC xenografts in vivo inhibited angiogenesis and VM, reduced primary tumor growth and lung metastasis of orthotopically implanted MDA-MB-468 TNBC cells, and markedly decreased lung metastases following intravenous injection of MDA-MB-231-4175 lung-tropic TNBC cells. Combined inhibition of angiogenesis, VM, and TNBC motility mediated by αEGFR-E-P125A is a promising strategy for the prevention of TNBC metastases.

WOS: 000407173800019, PubMed ID: 28278656, The oregano, Origanum onites L., essential oil (EO) was tested in laboratory behavioural bioassays for repellent activity against Amblyomma americanum (L.) and Aedes aegypti (L.). The O. onites EO was characterised using GC-FID and GC-MS. Carvacrol (75.70%), linalool (9.0%), p-cymene (4.33%) and thymol (1.9%) were the most abundant compounds. At a concentration of 0.413 mg oil/cm(2) of filter paper, O. onites EO repelled 100% of the ticks tested and at 0.103 mg oil/cm(2) of filter paper, 66.7% of the ticks were repelled. At 0.075 mg oil/cm(2) filter paper, thymol repelled 66.7% of the ticks compared to 28.7% by carvacrol at that same concentration. Against Ae. aegypti, O. onites EO was repellent at the minimum effective dosage (MED) of 0.011 (+/- 0.00) mg/cm(2) in the cloth patch assay compared to the reference control, N, N-dimethyl-3-methylbenzamide (DEET) with a MED = 0.007 +/- (0.003) mg/cm(2)., DWFP Research Program Grant - U.S. Department of Defense through the Armed Forces Pest Management Board, This work was supported in part by the DWFP Research Program Grant funded by the U.S. Department of Defense through the Armed Forces Pest Management Board.

In the NeurIPS 2018 Artificial Intelligence for Prosthetics challenge, participants were tasked with building a controller for a musculoskeletal model with a goal of matching a given time-varying velocity vector. Top participants described their algorithms in this paper. Many solutions use similar relaxations and heuristics, such as reward shaping, frame skipping, discretization of the action space, symmetry, and policy blending. However, each team implemented different modifications of the known algorithms by, for example, dividing the task into subtasks, learning low-level control, or by incorporating expert knowledge and using imitation learning.

Tunable complex oxide thin films have generated a lot of interest in recent years due to their potential to become a core technology in the new generation of multiple communications devices. These films are grown via different deposition methods and frequently postprocessed in order to enhance their dielectric properties. This paper discusses an alternative postprocessing technique where complex oxide thin films grown by radio frequency (RF) magnetron sputtering have been treated with an external microwave field instead of a conventional furnace. The treated films and untreated reference film were characterized for their microstructure and dielectric properties. The obtained results indicate a significant reduction in dielectric losses and leakage current in the microwave processed films as opposed to the untreated reference. The results are discussed together with potential additional benefits of the proposed approach.

Objective To evaluate the subjective and objective outcomes of Macroplastique® (MPQ) in women with stress urinary incontinence (SUI) secondary to intrinsic sphincter deficiency (ISD). Materials and Methods Following Institutional Review Board (IRB) approval, charts of non-neurogenic women with SUI secondary to ISD who underwent MPQ injection and had 6 months minimum follow-up were reviewed from a prospectively maintained database. Patients were divided into 3 groups: Naïve (Group I), Prior Anti-Incontinence Surgery (Group II), and combined Prior Bulking Agent and Anti-Incontinence Surgery (Group III). Data collected included SUI self-report, Urogenital Distress Inventory (UDI-6) Question 3, and VAS Quality of Life (QoL) Questionnaire scores at baseline and in follow-up. Three-dimensional ultrasound (3DUS) evaluated volume/configuration of MPQ. Success was defined after the last MPQ injection as a UDI-6 Question 3 score of 0 (dry) or 1, and no reoperation for SUI. Results From 2011-2017, 106 of 142 women met study criteria. At a median follow-up of 20 months (mean=26 months; range: 6-71), success rate was 41% for Group I, 40% for Group II, and 65% for Group III (p = 0.22). QoL scores were significantly improved over baseline in all groups. There was no significant difference in clinical outcome between the asymmetrical and symmetrical group on 3DUS. The completely dry rate was highest in Group III at 29%, compared to 4% for Group I and 15% for Group II (p = 0.05). Conclusion Macroplastique® improved subjective and objective outcome measures for SUI secondary to ISD as both a primary and secondary treatment option in women.

Core-shell scaffolds offer a promising regenerative solution to debilitating injuries to anterior cruciate ligament (ACL) thanks to a unique biphasic structure. Nevertheless, current core-shell designs are impaired by an imbalance between permeability, biochemical and mechanical cues. This study aimed to address this issue by creating a porous core-shell construct which favors cell infiltration and matrix production, while providing mechanical stability at the site of injury. The developed core-shell scaffold combines an outer shell of electrospun poly(caprolactone) fibers with a freeze-dried core of type I collagen doped with proteoglycans (biglycan, decorin) or glycosaminoglycans (chondroitin sulphate, dermatan sulphate). The aligned fibrous shell achieved an elastic modulus akin of the human ACL, while the porous collagen core is permeable to human mesenchymal stem cell (hMSC). Doping of the core with the aforementioned biomolecules led to structural and mechanical changes in the pore network. Assessment of cellular metabolic activity and scaffold contraction shows that hMSCs actively remodel the matrix at different degrees, depending on the core's doping formulation. Additionally, immunohistochemical staining and mRNA transcript levels show that the collagen-chondroitin sulphate formulation has the highest matrix production activity, while the collagen-decorin formulation featured a matrix production profile more characteristic of the undamaged tissue. Together, this demonstrates that scaffold doping with target biomolecules leads to distinct levels of cell-mediated matrix remodeling. Overall, this work resulted in the development of a versatile and robust platform with a combination of mechanical and biochemical features that have a significant potential in promoting the repair process of ACL tissue.

We have developed a novel T cell engaging bispecific antibody platform that utilizes the high avidity of IgM antibodies, but further combines this with the high affinity and specificity of IgG antibodies. By grafting the affinity matured binding domains of IgG antibodies onto the multimeric framework of an IgM antibody and fusing a CD3 binding single chain Fv domain to the J-chain, the resultant engineered IgM T cell bispecific antibody demonstrates strong binding to specific targets while limiting over-stimulation of engaged T cells. One of our bispecific IgM antibodies, IGM-2323, binds CD20 antigen with more than 1000 fold increased avidity and mediates complement dependent cytotoxicity (CDC) of CD20-expressing cells with greater than 100 fold higher potency when compared to the corresponding IgG bispecific. IGM-2323 also shows highly potent T cell dependent cytotoxicity, even on cells with very low cell surface expression of CD20 and on rituximab-resistant variants of Ramos cells. Significantly, IGM-2323 exhibits vastly reduced cytokine release in vitro and in vivo, with at least equivalent T cell dependent killing of CD20-expressing target cells, providing a potentially safer and more effective bispecific format than IgG-based T cell bispecifics. These data indicate that IgM-based bispecifics can induce T cell engagement and very potent cytotoxicity that can be dissociated from the cytokine release unlike what has been observed with other IgG-based bispecific antibodies. In vivo efficacy studies in humanized NSG mice indicated that doses as low as 3 μg/mouse cause complete B cell elimination. Similarly, bispecific IgM completely depletes circulating B cells in cynomolgus monkeys at doses of 300 μg per kg. Furthermore, in these primate studies, durable depletion of B cells in spleen and lymphoid tissues was noted without any observable adverse effects despite repeated doses at the highest dose tested, 25 mg/kg. Low levels of transiently increased circulating IL-6 and no increased levels of TNF-alpha and IFN-gamma were observed in these primate studies. These preclinical data demonstrate the potential for broad application of this novel modular IgM-based bispecific antibody format. A Phase I dose-escalation study of IGM-2323 is currently on-going in patients with relapsed/refractory Non-Hodgkin's Lymphoma. Citation Format: Ramesh Baliga, Keyu Li, Marigold Manlusoc, Paul R. Hinton, Dean C. Ng, Madeline H. Tran, Bing Shan, Hai Lu, Avneesh Saini, Sachi Rahman, Yuan C. Cao, Chitra Saraiya, Marvin S. Peterson, Stephen F. Carroll, Daniel S. Chen, Bruce A. Keyt. A bispecific IgM antibody format for enhanced T cell dependent killing with minimal cytokine release [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5664.

Today it seems that our total focus in the pharmaceutical industry is on developing new testing approaches, medications, and vaccines at lightning speed to fight COVID-19, the disease caused by the...