Spectroscopic identification of water emission from a main-belt comet.

Main-belt comets are small Solar System bodies located in the asteroid belt that repeatedly exhibit comet-like activity (that is, dust comae or tails) during their perihelion passages, strongly indicating ice sublimation1,2. Although the existence of main-belt comets implies the presence of extant water ice in the asteroid belt, no gas has been detected around these objects despite intense scrutiny with the world's largest telescopes3. Here we present James Webb Space Telescope observations that clearly show that main-belt comet 238P/Read has a coma of water vapour, but lacks a significant CO2 gas coma. Our findings demonstrate that the activity of comet Read is driven by water-ice sublimation, and implies that main-belt comets are fundamentally different from the general cometary population. Whether or not comet Read experienced different formation circumstances or evolutionary history, it is unlikely to be a recent asteroid belt interloper from the outer Solar System. On the basis of these results, main-belt comets appear to represent a sample of volatile material that is currently unrepresented in observations of classical comets and the meteoritic record, making them important for understanding the early Solar System's volatile inventory and its subsequent evolution.

Researcher Experience and Comfort With Telemedicine and Remote Patient Monitoring in Cancer Treatment Trials.

BACKGROUND: Since the onset of COVID-19, oncology practices across the US have integrated telemedicine (TM) and remote patient monitoring (RPM) into routine care and clinical trials. The extent of provider experience and comfort with TM/RPM in treatment trials, however, is unknown. We surveyed oncology researchers to assess experience and comfort with TM/RPM. METHODS: Between April 10 and June 1, 2022, we distributed email surveys to US-based members of the American Society of Clinical Oncology (ASCO) whose member records indicated interest or specialization in clinical research. We collected respondent demographic data, clinical trial experience, workplace characteristics, and comfort and experience with TM/RPM use across trial components in phase I and phase II/III trials. TM/RPM was defined as clinical trial-related healthcare and monitoring for patients geographically separated from trial site. RESULTS: There were 141 surveys analyzed (5.1% response rate). Ninety percent of respondents had been Principal Investigators, 98% practiced in a norural site. Most respondents had enrolled patients in phase I (82%) and phase II/III trials (99%). Across all phases and trial components, there was a higher frequency of researcher comfort compared to experience. Regarding remote care in treatment trials, 75% reported using TM, RPM, or both. Among these individuals, 62% had never provided remote care to trial patients before the pandemic. CONCLUSION: COVID-19 spurred the rise of TM/RPM in cancer treatment trials, and some TM/RPM use continues in this context. Among oncology researchers, higher levels of comfort compared with real-world experience with TM/RPM reveal opportunities for expanding TM/RPM policies and guidelines in oncology research.

The performance status gap in immunotherapy for frail patients with advanced non-small cell lung cancer.

PURPOSE: In advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitor (ICI) monotherapy is often preferred over intensive ICI treatment for frail patients and those with poor performance status (PS). Among those with poor PS, the additional effect of frailty on treatment selection and mortality is unknown. METHODS: Patients in the veterans affairs national precision oncology program from 1/2019-12/2021 who received first-line ICI for advanced NSCLC were followed until death or study end 6/2022. Association of an electronic frailty index with treatment selection was examined using logistic regression stratified by PS. We also examined overall survival (OS) on intensive treatment using Cox regression stratified by PS. Intensive treatment was defined as concurrent use of platinum-doublet chemotherapy and/or dual checkpoint blockade and non-intensive as ICI monotherapy. RESULTS: Of 1547 patients receiving any ICI, 66.2% were frail, 33.8% had poor PS (≥ 2), and 25.8% were both. Frail patients received less intensive treatment than non-frail patients in both PS subgroups (Good PS: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.51 - 0.88; Poor PS: OR 0.69, 95% CI 0.44 - 1.10). Among 731 patients receiving intensive treatment, frailty was associated with lower OS for those with good PS (hazard ratio [HR] 1.53, 95% CI 1.2 - 1.96), but no association was observed with poor PS (HR 1.03, 95% CI 0.67 - 1.58). CONCLUSION: Frail patients with both good and poor PS received less intensive treatment. However, frailty has a limited effect on survival among those with poor PS. These findings suggest that PS, not frailty, drives survival on intensive treatment.

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

The Landscape of Care for Women Veterans with Cancer: An Evidence Map.

BACKGROUND: Women are the fastest growing veteran group in the US and the number of women veterans (WVs) with cancer is rising; however, little is known about this population. Cancer care for WVs is complex and it is essential to understand their unique needs and care coordination challenges to provide evidence-based care. The purpose of this review is to map the quantity, distribution, and characteristics of literature describing cancer and its treatment among WVs. METHODS: We searched MEDLINE (via PubMed), Embase (Elsevier), and Web of Science Core Collection (Clarivate) from inception through January, 2024. Publications were eligible that reported gender-specific data on any aspect of cancer care among WVs. Data was abstracted by a single investigator with over-reading. RESULTS: Forty-six reports were included; 44 were observational and 19 had a women-only sample. There were no interventional reports and no qualitative reports had a patient sample. Breast cancer was the most commonly addressed (n = 19). There were six additional reports on sex-specific cancers. Many reports used large VA databases or previous trial data, creating the potential for patient overlap between reports. Among VA-specific areas of interest, only three reports evaluated the potential implications of racial differences and only two included a transgender population. No reports examined the effects of toxic exposures on cancer. Within the NCI Cancer Control Continuum, crosscutting areas were more commonly represented; over half (25) of the reports addressed epidemiology. There were few reports on focus areas and little overlap between focus and crosscutting areas. DISCUSSION: Existing literature provides an inadequate understanding of the population of WVs with cancer. There is scant information regarding the population of WVs with cancer, their care preferences or experiences, or how to best identify and address unmet healthcare needs. It is imperative to expand research to provide evidence-based care for this population.

A rapid decrease in the rotation rate of comet 41P/Tuttle-Giacobini-Kresák.

Cometary outgassing can produce torques that change the spin state of the cometary nucleus, which in turn influences the evolution and lifetime of the comet. If these torques increase the rate of rotation to the extent that centripetal forces exceed the material strength of the nucleus, the comet can fragment. Torques that slow down the rotation can cause the spin state to become unstable, but if the torques persist the nucleus can eventually reorient itself and the rotation rate can increase again. Simulations predict that most comets go through a short phase of rapid changes in spin state, after which changes occur gradually over longer times. Here we report observations of comet 41P/Tuttle-Giacobini-Kresák during its close approach to Earth (0.142 astronomical units, approximately 21 million kilometres, on 1 April 2017) that reveal a rapid decrease in rotation rate. Between March and May 2017, the apparent rotation period of the nucleus increased from 20 hours to more than 46 hours-a rate of change of more than an order of magnitude larger than has hitherto been measured. This phenomenon must have been caused by the gas emission from the comet aligning in such a way that it produced an anomalously strong torque that slowed the spin rate of the nucleus. The behaviour of comet 41P/Tuttle-Giacobini-Kresák suggests that it is in a distinct evolutionary state and that its rotation may be approaching the point of instability.

Actionable Genomic Alterations in Prostate Cancer Among Black and White United States Veterans.

Black Veterans have higher a incidence of localized and metastatic prostate cancer compared to White Veterans yet are underrepresented in reports of frequencies of somatic and germline alterations. This retrospective analysis of somatic and putative germline alterations was conducted in a large cohort of Veterans with prostate cancer (N = 835 Black, 1613 White) who underwent next generation sequencing through the VA Precision Oncology Program, which facilitates molecular testing for Veterans with metastatic cancer. No differences were observed in gene alterations for FDA approved targetable therapies (13.5% in Black Veterans vs. 15.5% in White Veterans, P = .21), nor in any potentially actionable alterations (25.5% vs. 28.7%, P =.1). Black Veterans had higher rates of BRAF (5.5% vs. 2.6%, P < .001) alterations, White Veterans TMPRSS2 fusions (27.2% vs. 11.7%, P < .0001). Putative germline alteration rates were higher in White Veterans (12.0% vs. 6.1%, P < .0001). Racial disparities in outcome are unlikely attributable to acquired somatic alterations in actionable pathways.

Genetics professionals are key to the integration of genetic testing within the practice of frontline clinicians.

PURPOSE: Genetic tests have become widely available. We sought to understand the use of genetic tests in the practice of frontline clinicians within the United States Department of Veterans Affairs (VA). METHODS: We administered a web-based survey to clinicians at 20 VA facilities. Physicians, nurse practitioners, physician assistants, and pharmacists were eligible. We excluded genetics providers and clinicians not seeing patients. We used multiple logistic regression to evaluate the associations between clinician characteristics and experience with genetics. RESULTS: The response rate was 11.3% (1207/10,680) and of these, 909 respondents were eligible. Only 20.8% of the respondents reported feeling prepared to use genetic tests and 13.0% of the respondents were currently ordering genetic tests; although, it was usually only 1 or 2 a year. Delivery of genetic tests without involving genetics providers was preferred by only 7.9% of the respondents. Characteristics positively associated with currently ordering genetic tests included practice in clinical and research settings, believing improving genetics knowledge could alter their practice, feeling prepared to use genetic tests, and referral of at least 1 patient to genetics in the past year. CONCLUSION: Most VA clinicians don't feel prepared to use genetic tests. Those with genetic testing experience are more likely to consult genetics providers. The demand for genetics providers should increase as frontline clinicians use genetic tests in their practice.

Mathematical modeling to understand the role of bivalent thrombin-fibrin binding during polymerization.

Thrombin is an enzyme produced during blood coagulation that is crucial to the formation of a stable clot. Thrombin cleaves soluble fibrinogen into fibrin, which polymerizes and forms an insoluble, stabilizing gel around the growing clot. A small fraction of circulating fibrinogen is the variant γA/γ', which has been associated with high-affinity thrombin binding and implicated as a risk factor for myocardial infarctions, deep vein thrombosis, and coronary artery disease. Thrombin is also known to be strongly sequestered by polymerized fibrin for extended periods of time in a way that is partially regulated by γA/γ'. However, the role of γA/γ'-thrombin interactions during fibrin polymerization is not fully understood. Here, we present a mathematical model of fibrin polymerization that considered the interactions between thrombin, fibrinogen, and fibrin, including those with γA/γ'. In our model, bivalent thrombin-fibrin binding greatly increased thrombin residency times and allowed for thrombin-trapping during fibrin polymerization. Results from the model showed that early in fibrin polymerization, γ' binding to thrombin served to localize the thrombin to the fibrin(ogen), which effectively enhanced the enzymatic conversion of fibrinogen to fibrin. When all the fibrin was fully generated, however, the fibrin-thrombin binding persisted but the effect of fibrin on thrombin switched quickly to serve as a sink, essentially removing all free thrombin from the system. This dual role for γ'-thrombin binding during polymerization led to a paradoxical decrease in trapped thrombin as the amount of γ' was increased. The model highlighted biochemical and biophysical roles for fibrin-thrombin interactions during polymerization and agreed well with experimental observations.

Risk factors of SARS-CoV-2 infection and complications from COVID-19 in lung cancer patients.

BACKGROUND: Identifying lung cancer patients at an increased risk of getting SARS-CoV-2-related complications will facilitate tailored therapy to maximize the benefit of anti-cancer therapy, while decreasing the likelihood of COVID-19 complications. This analysis aimed to identify the characteristics of lung cancer patients that predict for increased risk of death or serious SARS-CoV-2 infection. PATIENTS AND METHODS: This was a retrospective cohort study of patients with lung cancer diagnosed October 1, 2015, and December 1, 2020, and a diagnosis of COVID-19 between February 2, 2020, and December 1, 2020, within the Veterans Health Administration. Serious SARS-CoV-2 infection was defined as hospitalization, ICU admission, or mechanical ventilation or intubation within 2 weeks of COVID-19 diagnosis. For categorical variables, differences were assessed using Χ2 tests, while Kruskal-Wallis rank-sum test was used for continuous variables. Multivariable logistic regression models were fit relative to onset of serious SARS-CoV-2 infection and death from SARS-CoV-2 infection. RESULTS: COVID-19 infection was diagnosed in 352 lung cancer patients. Of these, 61 patients (17.3%) died within four weeks of diagnosis with COVID-19, and 42 others (11.9%) experienced a severe infection. Patients who had fatal or severe infection were older and had lower hemoglobin levels than those with mild or moderate infection. Factors associated with death from SARS-CoV-2 infection included increasing age, immune checkpoint inhibitor therapy and low hemoglobin level. CONCLUSIONS:  The mortality of lung cancer patients from COVID-19 disease in the present cohort was less than previously reported in the literature. The identification of risk factors associated with severe or fatal outcomes informs management of patients with lung cancer who develop COVID-19 disease.

Preclinical safety assessment of JNJ-10450232 (NTM-006), a structural analog of acetaminophen, that does not cause hepatotoxicity at supratherapeutic doses.

JNJ-10450232 (NTM-006) is a new molecular entity that is structurally related to acetaminophen. A comprehensive non-clinical safety program was conducted to support first-in-human and clinical efficacy studies based on preclinical data suggesting that the compound has comparable or enhanced antinociceptive and antipyretic efficacy without causing hepatotoxicity at supratherapeutic doses. No hepatic toxicity was noted in a mouse model sensitive to acetaminophen hepatotoxicity or in rats, dogs, and non-human primates in 28-day repeat dose toxicity studies at and above doses/exposures at which acetaminophen is known to cause hepatotoxicity. In the 28-day toxicity studies, all treatment-related findings were monitorable and reversible. Methemoglobinemia, which was observed in dogs and to a lesser extent in rats, is also observed with acetaminophen. This finding is considered not relevant to humans due to species differences in metabolism. Thyroid hypertrophy and hyperplasia were also observed in dogs and were shown to be a consequence of a species-specific UGT induction also demonstrated with increased thyroid hormone metabolism. Indirect bilirubin elevation was observed in rats as a result of UGT1A1 Inhibition. JNJ-10450232 (NTM-006) had no toxicologically relevant findings in safety pharmacology or genotoxicity studies. Together, these data supported progressing into safety and efficacy studies in humans.

Cost-Effectiveness of Tumor Genomic Profiling to Guide First-Line Targeted Therapy Selection in Patients With Metastatic Lung Adenocarcinoma.

OBJECTIVES: A cost-effectiveness analysis comparing comprehensive genomic profiling (CGP) of 10 oncogenes, targeted gene panel testing (TGPT) of 4 oncogenes, and no tumor profiling over the lifetime for patients with metastatic lung adenocarcinoma from the Centers for Medicare and Medicaid Services' perspective was conducted. METHODS: A decision analytic model used 10 000 hypothetical Medicare beneficiaries with metastatic lung adenocarcinoma to simulate outcomes associated with CGP (ALK, BRAF, EGFR, ERBB2, MET, NTRK1, NTRK2, NTRK3, RET, ROS1), TGPT (ALK, BRAF, EGFR, ROS1), and no tumor profiling (no genes tested). First-line targeted cancer-directed therapies were assigned if actionable gene variants were detected; otherwise, nontargeted cancer-directed therapies were assigned. Model inputs were derived from randomized trials (progression-free survival, adverse events), the Veterans Health Administration and Medicare (drug costs), published studies (nondrug cancer-related management costs, health state utilities), and published databases (actionable variant prevalences). Costs (2019 US$) and quality-adjusted life-years (QALYs) were discounted at 3% per year. Probabilistic sensitivity analyses used 1000 Monte Carlo simulations. RESULTS: No tumor profiling was the least costly/person ($122 613 vs $184 063 for TGPT and $188 425 for CGP) and yielded the least QALYs/person (0.53 vs 0.73 for TGPT and 0.74 for CGP). The costs per QALY gained and corresponding 95% confidence interval were $310 735 ($278 323-$347 952) for TGPT vs no tumor profiling and $445 545 ($322 297-$572 084) for CGP vs TGPT. All probabilistic sensitivity analysis simulations for both comparisons surpassed the willingness-to-pay threshold ($150 000 per QALY gained). CONCLUSION: Compared with no tumor profiling in patients with metastatic lung adenocarcinoma, tumor profiling (TGPT, CGP) improves quality-adjusted survival but is not cost-effective.

Chemoradiation treatment patterns among United States Veteran Health Administration patients with unresectable stage III non-small cell lung cancer.

BACKGROUND: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States (US). Among VHA patients, the rate of use of concurrent chemoradiation therapy (CCRT) among those with unresectable, stage III non-small cell lung cancer (NSCLC) is unknown. The objective was to report recent CCRT treatment patterns in VHA patients and identify characteristics associated with receipt of CCRT. METHODS: Using Department of Veteran Affairs (VA) Cancer Registry System data linked to VA electronic medical records, we determined rates of CCRT, sequential CRT (SCRT), radiation therapy (RT) only, chemotherapy (CT) only, and neither treatment. RESULTS: Among 4054 VHA patients who met study criteria, CCRT rates slightly increased from 44 to 50% between 2013 and 2017. Factors associated with decreased odds of CCRT receipt compared to any other treatment included increasing age (adjusted odds ratio [aOR] per 10 years = 0.67; 95% CI: 0.60-0.76) and Charlson-Deyo comorbidity score (aOR = 0.94; 95% CI: 0.91-0.97). White race was associated with increased odds of CCRT receipt (aOR = 1.24; 95% CI: 1.004-1.53). In a chart review sample of 200 patients, less than half (n = 85) had a documented reason for not receiving CCRT. Among these, 29% declined treatment, and 71% did not receive CCRT due to "not being a candidate" for reasons related to frailty or lung nodules being too far apart for radiation therapy. CONCLUSIONS: CCRT rates among VHA patients with unresectable, stage III NSCLC slightly increased from 2013 to 2017; however in 2017, only half were receiving CCRT. Older patients and those with multiple comorbidities were less likely to receive CCRT and even when controlling for these factors, non-white patients were less likely to receive CCRT.

Transportation as a barrier to colorectal cancer care.

BACKGROUND: Transportation barriers limit access to cancer care services and contribute to suboptimal clinical outcomes. Our objectives were to describe the frequency of Veterans reporting and the factors associated with transportation barriers to or from colorectal cancer (CRC) care visits. METHODS: Between November 2015 and September 2016, Veterans with incident stage I, II, or III CRC completed a mailed survey to assess perceived barriers to recommended care. Participants who reported difficulty with transportation to or from CRC care appointments were categorized as experiencing transportation barriers. We assessed pairwise correlations between transportation barriers, transportation-related factors (e.g., mode of travel), and chaotic lifestyle (e.g., predictability of schedules), and used logistic regression to examine the association between the reporting of transportation difficulties, distance traveled to the nearest Veterans Affairs (VA) facility, and life chaos. RESULTS: Of the 115 Veterans included in this analysis, 18% reported experiencing transportation barriers. Distance to the VA was not strongly correlated with the reporting of transportation barriers (Spearman's ρ = 0.12, p = 0.19), but chaotic lifestyle was both positively and significantly correlated with experiencing transportation barriers (Spearman's ρ = 0.22, p = 0.02). Results from the logistic regression model modestly supported the findings from the pairwise correlations, but were not statistically significant. CONCLUSIONS: Transportation is an important barrier to or from CRC care visits, especially among Veterans who experience greater life chaos. Identifying Veterans who experience chaotic lifestyles would allow for timely engagement in behavioral interventions (e.g., organizational skills training) and with support services (e.g., patient navigation).

Survival Advantage With Adjuvant Chemotherapy for Locoregionally Advanced Rectal Cancer: A Veterans Health Administration Analysis.

BACKGROUND: Adjuvant chemotherapy (AC) after chemoradiation (CRT) and surgery for locoregionally advanced rectal cancer (LARC) is a standard of care in the United States. This study examined the role, optimal regimen, and duration of AC using data from the largest integrated health system in the United States. PATIENTS AND METHODS: Using the Veterans Affairs Central Cancer Registry, patients with stage II-III rectal cancer diagnosed in 2001 through 2011 who received neoadjuvant CRT and surgery with or without AC were identified. Kaplan-Meier analysis, log-rank tests, and propensity score (PS) adjustment analysis were used to assess survival. RESULTS: A total of 866 patients were identified; 417 received AC and 449 did not (observation [OBS] group). Median follow-up was 109 months. Median disease-specific survival (DSS) was not reached. Six-year DSS was 73.7%; 79.5% for the AC group versus 68.0% for the OBS group. PS-matched analysis for DSS favored AC (P=.0002). Median overall survival (OS) was 90.8 months. Six-year OS was 56.7%; 64.3% for AC versus 49.6% for OBS. In PS-matched analysis, median OS was 117.4 months for AC and 74.3 months for OBS (P<.0001). A DSS advantage was seen when comparing ≥4 months with <4 months of AC (P=.023). No difference in DSS or OS was seen with single-agent versus multiagent AC. CONCLUSIONS: In this population of patients with LARC treated with neoadjuvant CRT and surgery, OS and DSS were improved among those treated with AC versus OBS. DSS benefits were seen with ≥4 months of AC. No additional benefit was observed with multiagent therapy. In the absence of phase III data, these findings support the use of AC for LARC.

A Mathematical Model of Bivalent Binding Suggests Physical Trapping of Thrombin within Fibrin Fibers.

Thrombin is an enzyme that plays many important roles in the blood clotting process; it activates platelets, cleaves coagulation proteins within feedback loops, and cleaves fibrinogen into fibrin, which polymerizes into fibers to form a stabilizing gel matrix in and around growing clots. Thrombin also binds to the formed fibrin matrix, but this interaction is not well understood. Thrombin-fibrin binding is often described as two independent, single-step binding events, one high-affinity and one low-affinity. However, kinetic schemes describing these single-step binding events do not explain experimentally-observed residency times of fibrin-bound thrombin. In this work, we study a bivalent, sequential-step binding scheme as an alternative to the high-affinity event and, in addition to the low-affinity one. We developed mathematical models for the single- and sequential-step schemes consisting of reaction-diffusion equations to compare to each other and to experimental data. We then used Bayesian inference, in the form of Markov chain Monte Carlo, to learn model parameter distributions from previously published experimental data. For the model to best fit the data, we made an additional assumption that thrombin was irreversibly sequestered; we hypothesized that this could be due to thrombin becoming physically trapped within fibrin fibers as they formed. We further estimated that ∼30% of thrombin in the experiments to which we compare our model output became physically trapped. The notion of physically trapped thrombin may provide new insights into conflicting observations regarding the speed of fibrinolysis. Finally, we show that our new model can be used to further probe scenarios dealing with thrombin allostery.

Increasing PET Use in Small Cell Lung Cancer: Survival Improvement and Stage Migration in the VA Central Cancer Registry.

Background: Accurate staging for small cell lung cancer (SCLC) is critical for determining appropriate therapy. The clinical impact of increasing PET adoption and stage migration is well described in non-small cell lung cancer but not in SCLC. The objective of this study was to evaluate temporal trends in PET staging and survival in the Veterans Affairs Central Cancer Registry and the impact of PET on outcomes. Patients and Methods: Patients diagnosed with SCLC from 2001 to 2010 were identified. PET staging, overall survival (OS), and lung cancer-specific survival (LCSS) were assessed over time. The impact of PET staging on OS and LCSS was assessed for limited-stage (LS) and extensive-stage (ES) SCLC. Results: From 2001 to 2010, PET use in a total of 10,135 patients with SCLC increased from 1.1% to 39.2%. Median OS improved for all patients (from 6.2 to 7.9 months), those with LS-SCLC (from 10.9 to 13.2 months), and those with ES-SCLC (from 5.0 to 7.0 months). Among staged patients, the proportion of ES-SCLC increased from 63.9% to 65.7%. Among 1,536 patients with LS-SCLC treated with concurrent chemoradiotherapy, 397 were staged by PET. In these patients, PET was associated with longer OS (median, 19.8 vs 14.3 months; hazard ratio [HR], 0.78; 95% CI, 0.68-0.90; P<.0001) and LCSS (median, 22.9 vs 16.7 months; HR, 0.74; 95% CI, 0.63-0.87; P<.0001) with multivariate adjustment and propensity-matching. In the 6,143 patients with ES-SCLC, PET was also associated with improved OS and LCSS. Conclusions: From 2001 to 2010, PET staging increased in this large cohort, with a corresponding relative increase in ES-SCLC. PET was associated with greater OS and LCSS for LS-SCLC and ES-SCLC, likely reflecting stage migration and stage-appropriate therapy. These findings emphasize the importance of PET in SCLC and support its routine use.

MYH9 E1841K Mutation Augments Proteinuria and Podocyte Injury and Migration.

Intronic variants of the MYH9 gene that encodes the nonmuscle myosin heavy chain IIA are associated with diabetic nephropathy in European Americans and with sickle cell disease-associated nephropathy. However, the causal functional variants of MYH9 have remained elusive. Rare missense mutations in MYH9 cause macrothrombocytopenia and are occasionally associated with development of nephropathy. The E1841K mutation is among the common MYH9 missense mutations and has been associated with nephropathy in some carriers. To determine the contribution of the E1841K mutation in kidney disease, we studied the effects of the E1841K mutation in mice subjected to high salt or angiotensin II (Ang II) as models of hypertension and in mice subjected to renal mass reduction as a model of CKD. Despite similar levels of BP among wild-type (MYH9+/+ ) mice and mice heterozygous (MYH9+/E1841K ) and homozygous (MYH9E1841K/E1841K ) for the mutation in each model, MYH9E1841K/E1841K mice exhibited mildly increased albuminuria in response to high salt; severe albuminuria, nephrinuria, FSGS, and podocyte foot effacement in Ang II-induced hypertension; and early mortality in the renal mass reduction model. Treatment with candesartan during Ang II-induced hypertension attenuated kidney disease development in MYH9E1841K/E1841K mice. In vitro, isolated primary podocytes from MYH9E1841K/E1841K mice exhibited increased lamellipodia formation and reorganization of F-actin stress fibers. Wound healing assays revealed that MYH9+/+ podocytes had the lowest migration rate, followed by MYH9+/E1841K then MYH9E1841K/E1841K podocytes. In conclusion, the MYH9 E1841K variant alters podocyte cytoskeletal structure and renders podocytes more susceptible to injury after a damaging stimulus.

NIST Standards for Measurement, Instrument Calibration, and Quantification of Gaseous Atmospheric Compounds.

There are many gas phase compounds present in the atmosphere that affect and influence the earth's climate. These compounds absorb and emit radiation, a process which is the fundamental cause of the greenhouse effect. The major greenhouse gases in the earth's atmosphere are carbon dioxide, methane, nitrous oxide, and ozone. Some halocarbons are also strong greenhouse gases and are linked to stratospheric ozone depletion. Hydrocarbons and monoterpenes are precursors and contributors to atmospheric photochemical processes, which lead to the formation of particulates and secondary photo-oxidants such as ozone, leading to photochemical smog. Reactive gases such as nitric oxide and sulfur dioxide are also compounds found in the atmosphere and generally lead to the formation of other oxides. These compounds can be oxidized in the air to acidic and corrosive gases and contribute to photochemical smog. Measurements of these compounds in the atmosphere have been ongoing for decades to track growth rates and assist in curbing emissions of these compounds into the atmosphere. To accurately establish mole fraction trends and assess the role of these gas phase compounds in atmospheric chemistry, it is essential to have good calibration standards. The National Institute of Standards and Technology has been developing standards of many of these compounds for over 40 years. This paper discusses the development of these standards.