PureTech (United States)

Abstract Novel treatment strategies are needed to overcome some of the current challenges related to treatment resistance and treatment latency within the psychiatric field. Recently, psilocybin has shown promise as a novel treatment of major depressive disorder. A single dose of psilocybin is associated with lasting changes in personality and mood. In parallel, various studies have indicated that microRNAs (miRNAs) are regulated after antidepressive interventions. Here, pigs were used to study the transcriptional profiles of miRNAs in the prefrontal cortex (PFC) and hippocampus (HIP), 1 day and 1 week after a single dose of psilocybin. A streamlined process was developed to adapt the Nanostring nCounter technology, specifically the Human v3b miRNA Assay panel, for compatibility with pig tissue samples. The mirmachine tool was used to select miRNAs with complete human-pig sequence conservation to make a conservative reannotation of pig microRNAs. Furthermore, different normalization strategies were employed. Utilizing this pipeline, dysregulation of 12 miRNAs in the PFC and 2 miRNAs in the HIP was ∂identified 1 day after psilocybin administration. Seven days after psilocybin administration, only 4 dysregulated miRNAs were observed in the HIP. Among the 18 identified miRNAs, 9 have previously been linked to depression. Notably, miR-212-3p and miR-107 displayed robust acute regulation across all four normalization strategies in the PFC. The two miRNAs are known to exert anti-inflammatory effects, mirroring previously reported effects of psilocybin. These results suggest that psilocybin may exert its acute and sustained molecular effects through the regulation of specific miRNAs in core brain areas of depression.

WSSC Water (WSSC) is among the largest water and wastewater utilities in the United States, serving approximately 1.8 million residents in Montgomery County and Prince George's County, Maryland. The backbone of WSSC's potable water transmission system is 145 mi of large diameter (36-in. and greater) prestressed concrete cylinder pipe (PCCP). For over ten years, WSSC implemented a condition assessment and asset management program to ensure the reliability of their PCCP transmission mains. WSSC Water employs a proactive approach to manage the condition of their PCCP transmission mains with a five year cycle multi-approach inspection followed by near-real-time pipeline acoustic fiber optic (AFO) monitoring. Inspection data and structural analysis together with AFO provide to WSSC up-to-date condition assessment information of each monitored PCCP to make informed proactive decisions. This paper will compare and discuss the results of four condition assessments performed in 2008, 2009, 2014, and 2020 on the same 48-in. PCCP Rockville Montgomery County High Zone transmission main. The 48-in. PCCP transmission main is comprised of approximately 31,895 ft of embedded cylinder PCCP (ECP) and approximately 517 ft of ductile iron pipe (DIP). The main connects the system from east to west providing redundancy between two WSSC's water treatment plants. A failure occurred in June 2008 resulting in an interruption of the service affecting residences and businesses primarily north of Randolph Road in Montgomery County. As a result, WSSC contracted Pure Technologies (Pure) to conduct a condition assessment of the transmission main. After the first condition assessment was completed in 2008 and the subsequent AFO monitoring technology installed for ongoing monitoring, this PCCP transmission main has been reinspected in 2014 and 2020 utilizing Pure's electromagnetic inspection technology. This paper will also evaluate the progression of deterioration, review the frequency of reinspection, analyze how repairs extended the service life of the 48-in. PCCP transmission main, share the lessons learned by WSSC's engineers executing the condition assessment every five years, and discuss what changes are ahead to improve the continuous success of the WSSC's PCCP program.

Pipeline condition assessment continues to gain in popularity as many reliable tools and technologies have proven reliable, yet even more technologies continue to be introduced to the pipeline industry. On a parallel path, although not as common, greater awareness and focus has been placed on the importance of valve reliability to ensure the safety and success of pipeline outages and pipeline inspections. Despite pipeline and valve assessments getting so much deserved, individual attention, the practice of proactively integrating the two inspections has not advanced as much as each individually. For example, performing Level I valve assessments to ensure valves are accessible and operable prior pipeline inspections is still too often overlooked. Furthermore, if a Level I assessment reveals that there is a problem with the gearing of the valve, whether it be a horizontal double disc gate valve, vertically oriented external geared gate valve, or a butterfly valve actuator, owners often fail to perform Level II assessment on the valve gearing or gear box to identify the problem and correct it in advance of the shutdown, complicating or compromising the pipeline inspection. Instead and oftentimes, the size of the shutdown is expanded, and the problematic control valve just replaced, wasting tens of thousands and often hundreds of thousands of dollars. Lastly, while pipelines are shut down, it is the opportune time to perform Level III condition assessment and any corrective maintenance on the butterfly valve discs and seats, or gate valve gates and tracks during pipeline inspections. This level of integration saves the owner significant maintenance and capital improvement program dollars that can be allocated to additional asset management program work.

Dallas Water Utilities (DWU) is a leader in conserving valuable water resources in North Texas due to their proactive approach to pipeline management. DWU has implemented an annual condition assessment program of buried pipelines, preventing catastrophic failures and large-scale water-loss events which have enabled DWU to utilize innovative leak detection and electromagnetic technologies to improve their ability to effectively manage resources. Since inception, DWU has documented over 5,900 leaks and repaired or replaced more than 303 individual pipes which were approaching failure. This paper will present an overview of DWU’s successful condition assessment approach and leak detection program along with results and a few lessons learned since the program’s inception 15 years ago.

Clinical value and utility of checkpoint inhibitors, a drug class targeting adaptive immune suppression pathways (PD-1, PDL-1, and CTLA-4), is growing rapidly and maintains status of a landmark achievement in oncology. Their efficacy has transformed life expectancy in multiple deadly cancer types (melanoma, lung cancer, renal/urothelial carcinoma, certain colorectal cancers, lymphomas, etc.). Despite significant clinical development efforts, therapeutic indication of approved checkpoint inhibitors are not as wide as the oncology community and patients would like them to be, potentially bringing into question their universal efficacy across tumor histologies. With the main goal of expanding immunotherapy applications, identifying of biomarkers to accurately predict therapeutic response and treatment related side-effects are a paramount need in the field. Specificities surrounding checkpoint inhibitors in clinic, such as unexpected tumor response patterns (pseudo- and hyper-progression), late responders, as well as specific immune mediated toxicities, complicate the management of patients. They stem from the complexities and dynamics of the tumor/host immune interactions, as well as baseline tumor biology. Search for clinically effective biomarkers therefore calls for a holistic approach, rather than implementation of a single analyte. The goal is to achieve dynamic and comprehensive acquisition, analyses and interpretation of immunological and biologic information about the tumor and the immune system, and to compute these parameters into an actionable, maximally predictive value at the individual patient level. Limitation delaying swift incorporation of validated immuno-oncology biomarkers span from standardized biospecimens acquisition and processing, selection of proficient biomarker discovery and validation methods, to establishing multidisciplinary consortiums and data sharing platforms. Multi-disciplinary efforts have already yielded some approved (PDL-1 and MSI-status) and other advanced tests (TMB, neoantigen pattern, and TIL infiltration rate). Importantly, clinical trial taskforces now recognize the imperative of the biomarker-driven trial design and execution, to enable translating biomarker discoveries into the clinical setting. This will ensure we utilize the “conspiracy” between the peripheral and intra-tumoral dynamic markers in shaping responses to checkpoint blockade, for the ultimate patient benefit.

The purpose of this review is to discuss the challenges associated with the development of nanoparticle-based quality drug products in adhering to the principles of quality by design (QbD) and defining appropriate quality parameters towards successful product development. With the advent of nanotechnology into the pharmaceutical field, the novel field of nanomedicine was born. Due to their unique properties in terms of size, conformation and targeted delivery, nanomedicines are able to overcome many drawbacks of conventional medicine. As nano-sized formulations have made their way into more and more therapies, it has became clear that these very unique properties create hurdles for nanomedicines in successfully traversing the regulatory pathways and there is a need to develop nanomedicines in a more controlled and consistent fashion. The elements of a QbD methodology explained in this review enable the development of nano-based formulations in a way that maximizes the possibility of success. The identification of critical quality attributes (CQA) of the drug product and its intermediates are discussed in detail with a focus on nanomaterial-based formulations. In conclusion, QbD and the identification and specification of CQAs at its core are critical to the design, development and growth of nanomaterials in pharmaceuticals.

With limited budgets and an aging system, infrastructure managers have increasingly sought cost-effective means to evaluate asset condition. While physical inspections can provide high quality data, they can be cost prohibitive at times. Pipe replacement is also expensive and replacing pipe that is still in good condition is not fiscally efficient. As such, an alternative method is to use available information to perform a desktop analysis, estimating the current conditions by exploring past performance records to help prioritize inspection and replacement. The spatial clustering of pipe breaks is an approach to observe the location of failures and identify regions with abnormally high failure rates. A clustering analysis fits well into a wider asset management framework, where the identified clusters act as possible evidence of distress which then might be targeted for physical inspection or replacement. We present an algorithm for scanning and clustering break data on pipe networks and demonstrate its application. Empirical findings show that the identified clusters can provide a high capture rate of future failures, proving itself a useful tool for decision support.

A comprehensive pipeline condition assessment allows utilities to make informed financial decisions, helping prioritize or defer maintenance, and capital spending. When you consider that the pipeline is a force main that services over 45,000 people and incudes a five-kilometer portion installed along the foreshore (intertidal zone) of the Pacific Ocean, a comprehensive pipeline condition assessment can also significantly reduce the risk of a failure with devastating consequences to the surrounding environment. The 750/820-millimeter force main was installed in the early 1980s and is nearly nine-kilometers long, servicing the communities of Courtenay and Comox, British Columbia. A recent risk assessment of a three-kilometer section along highly exposed coastline concluded that it was at high risk of failure, but a condition assessment was required to gain a better understanding on the condition. A rapid inspection plan collecting quantitative data on each pipe section with minimal operational downtime was essential. The resulting information could be used in a risk of failure analysis of the pipeline. The final deliverable from the project discusses the risk analysis of distressed pipes and their repair priorities. The information collected is assisting the CVRD with significant capital decisions and provides an enhanced safeguard against an environmental disaster.

The pharmacology, pharmacokinetics, and safety of modified mRNA formulated in lipid nanoparticles (LNPs) were evaluated after repeat intravenous infusion to rats and monkeys. In both species, modified mRNA encoding the protein for human erythropoietin (hEPO) had predictable and consistent pharmacologic and toxicologic effects. Pharmacokinetic analysis conducted following the first dose showed that measured hEPO levels were maximal at 6 hours after the end of intravenous infusion and in excess of 100-fold the anticipated efficacious exposure (17.6 ng/ml) at the highest dose tested.24 hEPO was pharmacologically active in both the rat and the monkey, as indicated by a significant increase in red blood cell mass parameters. The primary safety-related findings were caused by the exaggerated pharmacology of hEPO and included increased hematopoiesis in the liver, spleen, and bone marrow (rats) and minimal hemorrhage in the heart (monkeys). Additional primary safety-related findings in the rat included mildly increased white blood cell counts, changes in the coagulation parameters at all doses, as well as liver injury and release of interferon γ-inducible protein 10 in high-dose groups only. In the monkey, as seen with the parenteral administration of cationic LNPs, splenic necrosis and lymphocyte depletion were observed, accompanied with mild and reversible complement activation. These findings defined a well-tolerated dose level above the anticipated efficacious dose. Overall, these combined studies indicate that LNP-formulated modified mRNA can be administered by intravenous infusion in 2 toxicologically relevant test species and generate supratherapeutic levels of protein (hEPO) in vivo.