A Probody T Cell-Engaging Bispecific Antibody Targeting EGFR and CD3 Inhibits Colon Cancer Growth with Limited Toxicity.

T cell-engaging bispecific antibodies (TCB) are highly potent therapeutics that can recruit and activate cytotoxic T cells to stimulate an antitumor immune response. However, the development of TCBs against solid tumors has been limited by significant on-target toxicity to normal tissues. Probody therapeutics have been developed as a novel class of recombinant, protease-activated antibody prodrugs that are "masked" to reduce antigen binding in healthy tissues but can become conditionally unmasked by proteases that are preferentially active in the tumor microenvironment (TME). Here, we describe the preclinical efficacy and safety of CI107, a Probody TCB targeting EGFR and CD3. In vitro, the protease-activated, unmasked CI107 effectively bound EGFR and CD3 expressed on the surface of cells and induced T-cell activation, cytokine release, and cytotoxicity toward tumor cells. In contrast, dually masked CI107 displayed a >500-fold reduction in antigen binding and >15,000-fold reduction in cytotoxic activity. In vivo, CI107 potently induced dose-dependent tumor regression of established colon cancer xenografts in mice engrafted with human peripheral blood mononuclear cells. Furthermore, the MTD of CI107 in cynomolgus monkeys was more than 60-fold higher than that of the unmasked TCB, and much lower levels of toxicity were observed in animals receiving CI107. Therefore, by localizing activity to the TME and thus limiting toxicity to normal tissues, this Probody TCB demonstrates the potential to expand clinical opportunities for TCBs as effective anticancer therapies for solid tumor indications. SIGNIFICANCE: A conditionally active EGFR-CD3 T cell-engaging Probody therapeutic expands the safety window of bispecific antibodies while maintaining efficacy in preclinical solid tumor settings.

Acupuncture for Analgesia During Transurethral Resection of Bladder Tumor.

Background: Acupuncture has been widely studied, and theories regarding its analgesic mechanism of action have been proposed. It has been used for procedural analgesia; however, no reports of its use in urologic surgery have been reported. In this case report, we demonstrate how acupuncture can be used as an alternative to general anesthesia for transurethral resection of bladder tumor (TURBT). This may serve as an attractive option for bladder cancer patients with medical comorbidities, which predispose them to high risk for general anesthesia. Case Presentation: A 65-year-old Caucasian female with toxicant-induced loss of tolerance (TILT) was found to have a bladder mass. TURBT was discussed, and in light of her TILT syndrome, she elected to undergo the procedure with acupuncture in lieu of general anesthesia for fear of an adverse reaction. Acupuncture was performed by a trained practitioner with therapeutic needles placed in the ears, hands, abdomen, and lower extremities bilaterally. She was subsequently taken to the operating room where we performed a TURBT of a bladder tumor overlying the left ureteral orifice. The procedure was generally well tolerated and the patient experienced mild pain. There were no perioperative complications. The tumor was estimated to be 3 cm in largest diameter, and a total of 8 g of aggregate tissue was sent to our pathologists. Pathology analysis demonstrated adequate resection with detrusor muscle present in the sample. The bladder tumor was low-grade papillary urothelial cell carcinoma (Stage Ta). She has had tumor recurrence and has undergone repeat TURBT, but to date, she is 22 months free of bladder cancer. Conclusion: In this case report, we demonstrate that acupuncture is a safe and effective alternative to general anesthesia for patients undergoing TURBT. Since tobacco use is prevalent among bladder cancer patients, many of these individuals have associated medical comorbidities, which predispose them to high risk with general anesthesia. Therefore, acupuncture may serve as an attractive alternative for certain patients in this population.

Development and validation of the biobanking attitudes and knowledge survey (BANKS).

BACKGROUND: No validated multiscale instruments exist that measure community members' views on biobanking and biospecimen donation. This study describes the development and psychometric properties of the English-language BANKS (Biobanking Attitudes and Knowledge Survey). METHODS: The BANKS was created by item generation through review of scientific literature, focus groups with community members, and input from a community advisory board. Items were refined through cognitive interviews. Content validity was assessed through an expert panel review. Psychometric properties of the BANKS were assessed in a sample of 85 community members. RESULTS: The final BANKS includes three scales: attitudes, knowledge, and self-efficacy; as well as three single items, which evaluated receptivity and intention to donate a biospecimen for research. Cronbach α coefficients for two scales that use Likert response format indicated high internal consistency (attitudes: α, 0.88; self-efficacy: α, 0.95). Content validity indices were moderate, ranging from 0.69 to 0.89. Intention to donate blood and intention to donate urine were positively correlated with attitudes, knowledge, self-efficacy, and receptivity to learning more about biobanking (P values range from 0.029 to <0.001). CONCLUSIONS: The final BANKS shows evidence of satisfactory reliability and validity, is easy to administer, and is a promising tool to inform biospecimen research. Additional studies should be conducted with larger samples considering biospecimen donation to further assess the reliability and validity of the instrument. IMPACT: A valid and reliable instrument measuring community members' views about biobanking may help researchers evaluate relevant communication interventions to enhance understanding, intention, and actual biospecimen donation. A Spanish-language BANKS is under development.

Development and dematerialization: an international study.

Economic development and growth depend on growing levels of resource use, and result in environmental impacts from large scale resource extraction and emissions of waste. In this study, we examine the resource dependency of economic activities over the past several decades for a set of countries comprising developing, emerging and mature industrialized economies. Rather than a single universal industrial development pathway, we find a diversity of economic dependencies on material use, made evident through cluster analysis. We conduct tests for relative and absolute decoupling of the economy from material use, and compare these with similar tests for decoupling from carbon emissions, both for single countries and country groupings using panel analysis. We show that, over the longer term, emerging and developing countries tend to have significantly larger material-economic coupling than mature industrialized economies (although this effect may be enhanced by trade patterns), but that the contrary is true for short-term coupling. Moreover, we demonstrate that absolute dematerialization limits economic growth rates, while the successful industrialization of developing countries inevitably requires a strong material component. Alternative development priorities are thus urgently needed both for mature and emerging economies: reducing absolute consumption levels for the former, and avoiding the trap of resource-intensive economic and human development for the latter.

Long-term trends and opportunities for managing regional water supply and wastewater greenhouse gas emissions.

Greenhouse gas emissions are likely to rise faster than growth in population and more than double for water supply and wastewater services over the next 50 years in South East Queensland (SEQ), Australia. New sources of water supply such as rainwater tanks, recycled water, and desalination currently have greater energy intensity than traditional sources. In addition, direct greenhouse gas emissions from reservoirs and wastewater treatment and handling have potentially the same magnitude as emissions from the use of energy. Centralized and decentralized water supply and wastewater systems are considered for a scenario based upon a government water supply strategy for the next 50 years. Many sources of data have large uncertainties which are estimated following the IPCC Good Practice Guidelines. Important sources of emissions with large uncertainties such as rainwater tanks and direct emissions were identified for further research and potential mitigation of greenhouse gas emissions.

Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions.

Cytokines that signal through Class II receptors form a distinct family that includes the interferons and interleukin 10 (IL-10). Recent identification of several IL-10 homologs has defined a cytokine subfamily that includes AK155, IL-19, IL-20, IL-22, and IL-24. Within this subfamily, IL-19, IL-20, and IL-24 exhibit substantial sharing of receptor complexes; all three are capable of signaling through IL-20RA/IL-20RB, and IL-20 and IL-24 both can also use IL-22R/IL-20RB. However, the biological effects of these three cytokines appear quite distinct: immune activity with IL-19, skin biology with IL-20, and tumor apoptosis with IL-24. To more fully elucidate their interactions with the receptor complexes, we have performed a series of in vitro assays. Reporter, proliferation, and direct STAT activation assays using cell lines expressing transfected receptors revealed differences between the receptor complexes. IL-19 and IL-24 also exhibited growth inhibition on a cell line endogenously expressing all three receptor subunits, an effect that was seen at cytokine levels two orders of magnitude above those required for STAT activation or proliferation. These results demonstrate that, although this subclass exhibits receptor complex redundancy, there are differences in ligand/receptor interactions and in signal transduction that may lead to specificity and a distinct biology for each cytokine.