Discovery and targeting of a noncanonical mechanism of sarcoma resistance to ADI-PEG20 mediated by the microenvironment

PURPOSE: Many cancers lack argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme of arginine biosynthesis. This deficiency causes arginine auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 reexpression. This study examines the role of ASS1 silencing on tumor growth and initiation and identifies a noncanonical mechanism of resistance, aiming to improve clinical responses to ADI-PEG20. EXPERIMENTAL DESIGN: Tumor initiation and growth rates were measured for a spontaneous Ass1 knockout (KO) murine sarcoma model. Tumor cell lines were generated, and resistance to arginine deprivation therapy was studied in vitro and in vivo. RESULTS: Conditional Ass1 KO affected neither tumor initiation nor growth rates in a sarcoma model, contradicting the prevalent idea that ASS1 silencing confers a proliferative advantage. Ass1 KO cells grew robustly through arginine starvation in vivo, while ADI-PEG20 remained completely lethal in vitro, evidence that pointed toward a novel mechanism of resistance mediated by the microenvironment. Coculture with Ass1-competent fibroblasts rescued growth through macropinocytosis of vesicles and/or cell fragments, followed by recycling of protein-bound arginine through autophagy/lysosomal degradation. Inhibition of either macropinocytosis or autophagy/lysosomal degradation abrogated this growth support effect in vitro and in vivo. CONCLUSIONS: Noncanonical, ASS1-independent tumor resistance to ADI-PEG20 is driven by the microenvironment. This mechanism can be targeted by either the macropinocytosis inhibitor imipramine or the autophagy inhibitor chloroquine. These safe, widely available drugs should be added to current clinical trials to overcome microenvironmental arginine support of tumors and improve patient outcomes

What Point-of-Use Water Treatment Products Do Consumers Use? Evidence from a Randomized Controlled Trial among the Urban Poor in Bangladesh

BACKGROUND: There is evidence that household point-of-use (POU) water treatment products can reduce the enormous burden of water-borne illness. Nevertheless, adoption among the global poor is very low, and little evidence exists on why. METHODS: We gave 600 households in poor communities in Dhaka, Bangladesh randomly-ordered two-month free trials of four water treatment products: dilute liquid chlorine (sodium hypochlorite solution, marketed locally as Water Guard), sodium dichloroisocyanurate tablets (branded as Aquatabs), a combined flocculant-disinfectant powdered mixture (the PUR Purifier of Water), and a silver-coated ceramic siphon filter. Consumers also received education on the dangers of untreated drinking water. We measured which products consumers used with self-reports, observation (for the filter), and chlorine tests (for the other products). We also measured drinking water's contamination with E. coli (compared to 200 control households). FINDINGS: Households reported highest usage of the filter, although no product had even 30% usage. E. coli concentrations in stored drinking water were generally lowest when households had Water Guard. Households that self-reported product usage had large reductions in E. coli concentrations with any product as compared to controls. CONCLUSION: Traditional arguments for the low adoption of POU products focus on affordability, consumers' lack of information about germs and the dangers of unsafe water, and specific products not meshing with a household's preferences. In this study we provided free trials, repeated informational messages explaining the dangers of untreated water, and a variety of product designs. The low usage of all products despite such efforts makes clear that important barriers exist beyond cost, information, and variation among these four product designs. Without a better understanding of the choices and aspirations of the target end-users, household-based water treatment is unlikely to reduce morbidity and mortality substantially in urban Bangladesh and similar populations

Therapeutic arginine starvation in ASS1-deficient cancers inhibits the Warburg effect

Argininosuccinate Synthetase 1 deficiency induces dependence on extracellular arginine for continued cellular growth and survival. Arginine starvation inhibits the Warburg effect and diverts glucose into serine biosynthesis, while simultaneously increasing glutamine metabolism via the tricarboxylic acid cycle. Simultaneous arginine deprivation and inhibition of the subsequent metabolic adaptations induce synthetic lethality

Tele-Untethered: Telemedicine Without Waiting Rooms

Background and objectivesTelemedicine bridges the gap between care needs and provider availability. The value of telemedicine can be eclipsed by long wait times, especially if patients are stuck in virtual waiting rooms. UCSD Tele-Untethered allows patients to join visits without waiting in virtual waiting rooms. Tele-Untethered uses a text-to-video link to improve clinic flow, decrease virtual waiting room reliance, improve throughput, and potentially improve satisfaction.MethodsThis institutional review board (IRB)-approved quality improvement pilot (IRB #210364QI) included patients seen in a single vascular neurology clinic, within the pilot period, if they had a smartphone/cell phone, and agreed to participate in a flexible approach to telehealth visits. Standard work was disseminated (patient instructions, scripting, and workflows). Patients provided a cell phone number to receive a text link when the provider was ready to see them. Metrics included demographics, volumes, visit rates, percentage seen early/late, time savings, and satisfaction surveys.ResultsOver 2.5 months, 22 patients were scheduled. Of those arriving, 76% were "Tele-Untethered" and 24% were "Standard Telemedicine." Text-for-video link was used for 94% of Tele-Untethered. Fifty-five percent were seen early. There was a 55-minute-per-session time savings.ConclusionThis UCSD Tele-Untethered pilot benefitted patients by allowing scheduling flexibility while not being tied to a "virtual waiting room." It benefited providers as it allowed them to see patients in order/not tied to exact times, improved throughput, and saved time. Even modest time savings for busy providers, coupled with Lean workflows, can provide critical value. High Tele-Untethered uptake and use of verbal check-in highlight that patients expect flexibility and ease of use. As our initial UCSD Tele-Untethered successes included patient flexibility and time savings for patients and providers, it can serve as a model as enterprises strive for optimal care and improved satisfaction. Expansion to other clinic settings is underway with a mantra of "UCSD Tele-Untethered: Your provider can see you now.

COSMIC Variance in Binary Population Synthesis

The formation and evolution of binary stars is a critical component of several fields in astronomy. The most numerous sources for gravitational wave observatories are inspiraling and/or merging compact binaries, while binary stars are present in nearly every electromagnetic survey regardless of the target population. Simulations of large binary populations serve to both predict and inform observations of electromagnetic and gravitational wave sources. Binary population synthesis is a tool that balances physical modeling with simulation speed to produce large binary populations on timescales of days. We present a community-developed binary population synthesis suite: COSMIC which is designed to simulate compact-object binary populations and their progenitors. As a proof of concept, we simulate the Galactic population of compact binaries and their gravitational wave signal observable by the Laser Interferometer Space Antenna (LISA). We find that $\sim10^8$ compact binaries reside in the Milky Way today, while $\sim10^4$ of them may be resolvable by LISA.Comment: reflects the version submitted to ApJ; 17 pages, 2 Tables, 4 Figures; corrects typo in SNR calculatio

Malignancy validation in a United States registry of rheumatoid arthritis patients

<p>Abstract</p> <p>Background</p> <p>Physician reporting is commonly used to ascertain adverse events or outcomes measured in epidemiologic studies. However, little is known on the accuracy of physician reported malignancies compared to pertinent medical record review in large cohort studies.</p> <p>Methods</p> <p>The Consortium of Rheumatology Researchers of North America (CORRONA) registry gathers physician-completed questionnaires for rheumatoid arthritis (RA) patients, including request for information on incident malignancies, approximately every three months. For incident malignancies reported from October 1st, 2001, through December 31st, 2007, we retrospectively requested completion of a Targeted Adverse Event (TAE) form for additional information as well as primary source documents to adjudicate the malignancy reports. CORRONA has employed a prospective request for source documentation for these events since 2008. We classified each malignancy as definite, probable, possible, or not a malignancy.</p> <p>Results</p> <p>From 20,837 RA patients enrolled in CORRONA, 461 incident malignancies were initially reported on physician questionnaires. After review of returned source documents with adjudication, 234 were deemed definite, 69 probable, 101 possible, and 57 not an incident malignancy. The positive predictive value (PPV) of initial physician report of a malignancy <it>versus</it> “definite or probable” malignancy based on adjudication was 0.66 (95% CI 0.61 - 0.70). The PPV was 0.68 (95% CI 0.63 – 0.72) when the subsequent TAE form also confirmed the presence of malignancy. When possible malignancies were included, the PPV of physician-reported malignancies without a subsequent TAE form increased to 0.86 (0.83 – 0.89), and with a subsequent TAE form, 0.89 (0.85-0.91).</p> <p>Conclusion</p> <p>Twelve percent of initial physician reports of incident malignancy could not be confirmed with review of source documents. The most common reason for lack of confirmation was inability to obtain documents or insufficient data in source materials. These results suggest that timely collection of relevant medical records and an adjudication process are required to improve the accuracy of cancer reporting in epidemiologic studies.</p