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Supplementary Fig. S1 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

Supplementary Table S1 from Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through IGF-I receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-II binding and by inducing cell surface receptor down-regulation via internalization and degradation, with the extracellular and intracellular domains of IGF-IR being differentially affected by the proteasomal and lysosomal inhibitors. In vitro, h10H5 exhibits antiproliferative effects on cancer cell lines. In vivo, h10H5 shows single-agent antitumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models and even greater efficacy in combination with the chemotherapeutic agent docetaxel or an anti–vascular endothelial growth factor antibody. Antitumor activity of h10H5 is associated with decreased AKT activation and glucose uptake and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors and furthermore illustrate a new method of monitoring its activity noninvasively in vivo via 2-fluoro-2-deoxy-d-glucose-positron emission tomography imaging. [Mol Cancer Ther 2008;7(9):2599–608]

Background: Despite the success of multiple HER2-targeted agents in HER2+ breast cancer (BC), resistance remains a challenge and novel therapies are needed. DHES0815A is a THIOMABTM antibody-drug conjugate consisting of a humanized IgG1 anti-HER2 monoclonal antibody (mAb) conjugated to the DNA alkylating agent PBD-MA. The reduced potency of PBD-MA compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of the mAb to a HER2 epitope distinct from trastuzumab and pertuzumab was designed to enable combination therapy with existing HER2 therapies. Methods: This first-in-human, Phase I, open-label, multicenter, dose escalation study used a 3+3 dose escalation design to assess the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of DHES0815A in patients with metastatic HER2-positive BC refractory to established therapies (NCT03451162). DHES0815A (0.6-6.0 mg/kg) was administered intravenously every 3 weeks (Q3W) until intolerable toxicity or disease progression. Results: A total of 14 patients were treated with DHES0815A; all had ≥3 prior lines of therapy. Thirteen patients discontinued treatment due to progressive disease (43%), adverse events (AE; [29%]) symptomatic deterioration (14%) or other (7%); 1 patient remains on treatment. DHES0815A was initially well-tolerated for doses up to 2.4 mg/kg. At 4.0 mg/kg and 6.0 mg/kg, the first dose was also well-tolerated with no dose limiting toxicities, however, following 3 or more cycles at 4.0 mg/kg or 2 or more cycles at 6.0 mg/kg, safety events involving skin, eyes, and lung emerged. Skin events were reported in 50% of patients (all doses) and related events occurring in n≥2 patients included pruritus (36%), rash (36%), and skin hyperpigmentation (21%). Ocular toxicities were reported in 57% and related events occurring in n≥2 patients included photophobia (21%), conjunctivitis, eye pain, and dry eye (each 14%). Lung toxicities were reported in 36% of patients; events occurring in n≥2 included pneumonitis (14%). Other related skin, ocular, and pulmonary events occurring in 1 patient (7%) included palmar-plantar erythrodysaesthesia, macular rash, blurred vision, eyelid edema, periorbital edema, blepharitis, punctate keratitis, wheezing, allergic rhinitis, and pneumothorax. Most events were grade 1 or 2 although 3 patients experienced grade 3 ocular events (blepharitis, eye pain, photophobia). Due to these AEs, DHES0815A dose was decreased to 2.4 mg/kg Q3W for all enrolled patients and accrual was stopped. All 5 patients receiving doses of 4.0 mg/kg and 6.0 mg/kg discontinued due to AEs. At lower doses, 1 patient receiving 2.4 mg/kg developed grade 2 rash at Cycle 21 and 1 patient receiving 1.2 mg/kg developed grade 1 rash, pruritis, and skin hyperpigmentation between Cycles 28-30. Nonlinear PK of antibody-conjugated PBD-MA (acPBD-MA) was observed due to target mediated drug disposition at 0.6, 1.2, and 2.4 mg/kg; PK approached linear at 4.0 mg/kg. Minimal systemic exposure of unconjugated PBD-MA was observed. Overall, 1 patient (7%) in the 1.2 mg/kg cohort achieved a confirmed complete response. As of 10Jun21, this patient remains on study after more than 32 months on treatment. Ten patients (86%) showed a confirmed best overall response of stable disease (86%). Conclusion: Despite some anti-tumor activity observed with DHES0815A, development in HER2-positive BC has been discontinued due to safety concerns and the narrow therapeutic window. Toxicities observed in skin, lung, and eyes are clinically apparent only after repeated dose administration. If future exploration of PBD-MA-based constructs is performed in the clinic, close monitoring for delayed toxicities is warranted. Citation Format: Ian Krop, Erika Hamilton, Kyung Hae Jung, Shanu Modi, Kevin M Kalinsky, Gail Phillips, Rong Shi, Sharareh Monemi, Michael Mamounas, Ola Saad, Voleak Choeurng, Renee Commerford, Eunpi Cho, Alexander Ungewickell, Patricia LoRusso. A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-25.

Vision Australia Radio (VAR) is part of the Australian Radio for the Print Handicapped (RPH) community radio network providing a radio reading service to listeners with a vision impairment. Like ma...

Site-specific conjugation of small molecules to antibodies represents an attractive goal for the development of more homogeneous targeted therapies and diagnostics. Most site-specific conjugation strategies require modification or removal of antibody glycans or interchain disulfide bonds or engineering of an antibody mutant that bears a reactive handle. While such methods are effective, they complicate the process of preparing antibody conjugates and can negatively impact biological activity. Herein we report the development and detailed characterization of a robust photoaffinity cross-linking method for site-specific conjugation to fully glycosylated wild-type antibodies. The method employs a benzoylphenylalanine (Bpa) mutant of a previously described 13-residue peptide derived from phage display to bind tightly to the Fc domain; upon UV irradiation, the Bpa residue forms a diradical that reacts with the bound antibody. After the initial discovery of an effective Bpa mutant peptide and optimization of the reaction conditions to enable efficient conjugation without concomitant UV-induced photodamage of the antibody, we assessed the scope of the photoconjugation reaction across different human and nonhuman antibodies and antibody mutants. Next, the specific site of conjugation on a human antibody was characterized in detail by mass spectrometry experiments and at atomic resolution by X-ray crystallography. Finally, we adapted the photoconjugation method to attach a cytotoxic payload site-specifically to a wild-type antibody and showed that the resulting conjugate is both stable in plasma and as potent as a conventional antibody-drug conjugate in cells, portending well for future biological applications.

During the Global Financial Crisis (GFC) of 2008, the financial press attracted criticism for its coverage: specifically that it did not provide any forewarnings to the general public; that it lacked sufficient scepticism when reporting on financial and economic trends; and that reporters were too close to the sources they used for information. This paper argues the GFC represents only the latest manifestation of dissatisfaction with the financial press, with similar concerns being raised in previous financial crises such as the recession of the late 1990s and the Dot Com boom in 2000. The paper presents the results of a longitudinal tri-nation quantitative and qualitative content analysis of the reportage in three mainstream newspapers in the United States, the United Kingdom, and Australia across three decades, along with industry insights provided by interviews with reporters in each of the countries studied. The interviews and empirical evidence indicate there has been a decline in mainstream financia...

Purpose– This paper aims to demonstrate how action research methodologies can help to define and clarify the pedagogical role of the supervisor in production-based research (PBR). A major challenge in supervising practice-related research is trying to disentangle and articulate the theory embedded within practical projects. In journalism, which is still a relatively new discipline in academe, supervisors and students are often operating in under-theorised areas with no pre-existing theoretical roadmap. Action research has shown itself to be a useful methodology for structuring and explaining practice-related research, which in journalism would encompass PBR in the field. This paper shows how the action research paradigm is equally useful in describing and clarifying the supervisor’s role in these sorts of projects.Design/methodology/approach– The paper looks first at practice-related research and the main challenges for candidates and supervisors in trying to align PBR with academic paradigms. Using examples from the author’s experience in supervising journalism research, it then illustrates how the main supervision tasks of project management, research mentoring and the writing-up process fit into the action research model.Findings– In reflecting on the dynamics between candidates and supervisors in PBR, this paper shows how supervision of production-based PhDs is a dynamic research process in itself, presenting opportunities for pedagogical reflection.Originality/value– The paper helps to clarify the role of the supervisor in this specialist research area which is still trying to establish itself within academe. It provides one way for supervisors to conceptualise their experiences and so contribute to a corpus of knowledge on which others can draw and build. By showing how the action research methodology applies to the supervision process in production-based research (PBR), this paper articulates a way for supervisors to understand and manage their role in this still-evolving research area. Building on previous scholarship and applying this knowledge to journalism production, the paper shows how action research may provide a way of addressing many of the issues and dilemmas others have encountered and identified in their pedagogical practice.

Australian journalism schools are full of students who have never met an Aboriginal or Torres Strait Island person and who do not know their history. Journalism educators are ill-equipped to redress this imbalance as a large majority are themselves non-Indigenous and many have had little or no experience with the coverage of Indigenous issues or knowledge of Indigenous affairs. Such a situation calls for educational approaches that can overcome these disadvantages and empower journalism graduates to move beyond the stereotypes that characterize the representation of Indigenous people in the mainstream media. This article will explore three different courses in three Australian tertiary journalism education institutions, which use Work-Integrated Learning Approaches to instil the cultural competencies necessary to encourage a more informed reporting of Indigenous issues. The findings from the three projects illustrate the importance of adopting a collaborative approach by industry, the Indigenous community and educators to encourage students’ commitment to quality journalism practices when covering Indigenous issues.

A recent study of ethnic diversity in Australia's television news showed that diversity of race, culture and religion is largely absent from the news services, unless people from ethnic minorities are posing a social problem of some kind. A parallel study of Australia's nightly current affairs programs has yielded similar results: like news, they represent Australia as an ‘Anglo’ nation. When ethnic minorities are featured, they tend to occupy peripheral roles, and where they are allowed a central role, it is usually to be shown as threatening and menacing to the Anglo mainstream. The industry codes of practice explicitly state the standards that should apply in reporting on race, culture and religion, yet only the public broadcaster, the ABC, follows the guidelines in the representation of diversity. The reporting practices on the commercial stations deliberately or unwittingly encourage a sense of racial hierarchy in which the Anglo dominates.

The purpose of this study was to describe the reported perceptions of six midwife participants at different stages of their engagement in a multiphase process of adopting a new model of prenatal care. Midwives were interviewed at five different stages during the process of implementing CenteringPregnancy, a model of group prenatal care. The research methodology used in this study was phenomenology. The conceptual framework for exploring the participants’ perceptions was based on the Institute for Healthcare Improvement’s patient-centered model and on the International Institute for Restorative Practices’ empowerment model. The five themes that emerged from the midwives’ experiences mirrored the stages of change health education model. Suggestions for the implementation and sustainability of the CenteringPregnancy model of care are provided based on the five themes that emerged from this study’s findings.

The internet has provided us with a global laboratory to watch community-building in action. However, its role in the virtual universe is one that the more humble radio has had at the local community level since its inception. As soon as one-to-one communication gave way to one-to-many broadcasting, community-building began, based on the shared listening experience — ranging from families gathering around the wireless to local or national audiences tuning in simultaneously. Talkback made radio interactive by bringing the listener into the program, but it also gave program-makers the chance to gain first-hand experience of who was actually out there. This paper describes a radio talkback experiment which unexpectedly exposed the power of the relationship audiences can build with radio. Based on a ‘can you help’ formula, the program found passionate drivers within its audience members to belong, to bond, and to do good works that contribute to the social good.

The Broadcasting Services Act 1992 ushered in a new hands-off approach by government which, in the case of radio, permitted commercial broadcasters to double their investments in individual markets through the two-station policy while removing any onerous commitments to local content. Since then, there has been concern about the flow-on effect this may have had, with Peter Collingwood's 1997 study of commercial radio confirming that levels of local content were reducing as levels of networked content were increasing. He bemoaned the fact that a by-product of the self-regulatory regime was a reduction in the amount of publicly available information against which performance could be gauged. Since 1992, only one detailed study of local radio news has been done, Graeme Turner's 1996 examination of radio and television news in the Brisbane market. Now a parallel study has been conducted in Perth, giving an insight into localism and networking six years later.

The uninvited guest from the unremembered past: an exploration of the unconscious transmission of trauma across the generations, by Prophecy Coles, London, Karnac, 2011, 112 pp., £14.99, ISBN: 978 ...

Abigail Thomas, Research Manager, ABC New Media, reflects on developments in new media audience research since the 2001 Ratings in Transition seminar. Abigail Thomas was interviewed by Gail Phillips.

In this Interview with Gail Phillips, Ian Muir reflects on the developments in the audience measurement industry since the Ratings in Transition seminar held in 2001.

There is considerable ferment surrounding audience measurement systems in Australia and internationally (Balnaves, O'Regan and Sternberg, 2002). This article identifies the range and sources of this ferment. It pinpoints several pressure points such as the constitution of ratings panels and the problems of survey fatigue in a fragmenting media environment. Consideration is also given to ‘next generation’ ratings measurement technologies such as the personal people meter (PPM) and their likely impact upon the industry and its norms, and new media formats such as the personal video recorder (PVR) and the problems and opportunities they create for audience measurement systems.

While the broadcast industry as a whole may be abuzz with the potential for new survey methodologies, the Australian commercial radio sector retains a more pragmatic perspective. Joan Warner, Chief Executive Officer for the commercial radio industry body Commercial Radio Australia, talks about radio's place in the multimedia environment and the hurdles new survey technologies will have to overcome to deliver the sort of data the industry will be prepared to trust. Joan was interviewed by Gail Phillips.

My contribution to this chapter is the result of a long spell of thinking and practising psychoanalytic psychotherapy with children, adolescents and their parents. Furthermore, it is the distillation of years of work with a series of trainee and qualifi ed child psychotherapists I was fortunate to work with, who have challenged and inspired me. I will not acknowledge them here; I trust that they know who they are. (I hope their ‘true self’ allows them to distance themselves from any feeling of shared good fortune in our collaboration!) One of them, Gail Phillips (GP), is the co-author of this chapter.

In the Halton District School Board we appreciate the power of relationships, not only at an interpersonal level, but also among all aspects of the teacher/learner dynamic. Our Partners in the Classroom program is designed to optimize the use of these relationships to ease the transition to the teaching profession for our newest members of the Halton family while at the same time modelling the behaviours that we want to see across our system.

Ultrasonography has proved to be a highly useful method for detecting testicular lesions, correlating them with clinical findings, and indicating whether scrotal masses are caused by fluid or by solid tissue. It has not been possible, however, to distinguish spermatic cord torsion from epididymitis.

Computed tomography (CT) was performed in 9 consecutive cases of primary gastric neoplasm. Lesions were surgically or endoscopically proved; cross-sectional images are correlated to specific histopathology in each case. The CT images of leiomyoma and leiomyoblastoma are characterized as models of pure bulging intramural growth resulting in a lunate contrast distribution when imaged in the cross-sectional plane. In 5 cases of lymphoma, distortion of the contrast-filled hollow viscus is relatively consistent. Nodular growth is reflected on the CT image as a series of digitations encroaching on the opacified portion of the gastric lumen. Image pattern recognition, relative to histopathology, is of more than academic interest since endoscopy is frequently unreliable in cases of submucosal and exophytic pathology. Further, biopsy of such lesions is commonly nondiagnostic as a result of random choice of biopsy site or inadequate depth of tissue sample. Additionally, this report includes images of lesions that simulate the primary gastric pathology and may be a source of erroneous interpretation. These include: pseudocyst of the pancreas (2 cases) and enlargement of the left lobe of the liver with encroachment on the gastric lumen (1 case). Image specificity on CT examination is increasingly essential to diagnosis and surgical planning.

Adult cystic fibrosis (CF) patients are increasingly diagnosed with hepatic cirrhosis, cholecystitis, and cholelithiasis. A continuing diagnostic problem is the early detection of cirrhosis prior to diffuse liver involvement. Sonography has been used in evaluating the pancreas, gallbladder, liver, and spleen in cystic fibrosis patients. We used a real-time mechanical sector scanner to study the portal veins in adult CF patients randomly selected from our CF population and correlated the portal vein diameters with liver function studies. A measurement greater than 12 mm was interpreted as a probable sign of portal hypertension. Of 21 patients studied, 14 had portal veins that measured greater than 12 mm, and 12 patients had (although not necessarily at the time of the exam) elevated serum alkaline phosphatase levels. Three patients had associated splenomegaly and thrombocytopenia, and 10 patients also exhibited cholelithiasis and abnormal gallbladders on sonography. Initial results indicate that portal vein measurement may be a sensitive indicator of early portal hypertension. Sonography may, thus, isolate patients at high risk for possible future complications. Serial sonograms can be performed easily in evaluating the progress of liver disease.

Fine needle aspiration biopsy is a highly accurate cytologic technique in the differentiation of benign vs. malignant disease. After careful localization with the ultrasound beam, a 22 gauge 0.6 mm needle is used to obtain four to five cell samples. Seventy percutaneous fine needle aspiration biopsies were performed on pancreatic, liver, renal, chest, pelvic, pancreatic nodes, subcutaneous nodules, and other retroperitoneal masses. Ninety-three percent accuracy was obtained with no complications. Studies in four patients with carcinoma of the tail of the pancreas were falsely negative for malignant cells; all four patients had desmoplastic tumors. Complications of hemorrhage, tumor seeding, infection, fistula formation, and pain encountered with other methods and using larger bore needles have not been found with the fine needle technique. It is a safe, accurate method that can be performed as an out-patient procedure.

We report 4 cases of peripelvic extravasation caused by tumor obstruction of the ureter. A urinoma developed in 3 of the 4 cases. Review of the literature reveals only 5 previously reported cases of peripelvic extravasation secondary to tumor obstruction of the urinary tract. We discuss the mechanics of peripelvic extravasation and urinoma formation, and conclude that tumor obstruction of the ureter must be considered in all cases of peripelvic extravasation.

Eleven cases of sonographically detected metastatic disease to the gallbladder are reported. This paper represents the first comprehensive review of the ultrasonographic findings in this not infrequently encountered disease process. Four distinctive sonographic diagnostic patterns have evolved and are described. The suspicion of metastatic tumors in the gallbladder should be raised, particularly in the presence of focal gallbladder wall thickening in association with nonshadowing intraluminal soft tissue masses. In contrast to primary carcinomas of the gallbladder, cholelithiasis usually is absent. The differential diagnosis, which includes various benign conditions of the gallbladder, is discussed.