A Phase II Trial of Atezolizumab Plus Carboplatin Plus Pemetrexed Plus Bevacizumab in the Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung Cancer: Big Ten Cancer Research Consortium (BTCRC)- LUN 17-139.

INTRODUCTION: LUN17-139 evaluated the safety and efficacy of Atezolizumab (A) plus Carboplatin (C) plus Pemetrexed (Pem) plus Bevacizumab (B) (ACBPem) in treatment naïve patients with stage IV non-squamous non-small cell lung cancer (Ns-NSCLC). PATIENTS AND METHODS: In this multicenter, single-arm phase II trial, all patients received A (1200-mg, D1) + C (AUC 5, D1) + Pem (500-mg/m2, D1) + B (15-mg/kg D1) q3 week x4. If no PD (progressive disease), patients received maintenance ABPem until PD or intolerable side effects. The primary endpoint was progression-free survival (PFS). The positive PFS result was considered as PFS>6m (historical control). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) defined by complete response (CR) + partial response (PR) + stable disease (SD) ≥ 2 months, overall survival (OS), and safety. RESULTS: Thirty patients were enrolled from November 2018 to October 2020. The study was closed early due to 3 patient deaths, possibly related to treatment. Median age 64 (range 38-83); Men/Women 20/10; PD-L1 TPS < 1%/1-49%/ ≥ 50% (8/15/7). The median follow-up was 20.3 months ( 1-28.1). ORR 42.9% (95% CI, 24.5-62.8%), DCR 96.4% (95% CI, 81.7-99.9%). The median PFS and OS were 11.3m (5.5-14.9,P > .05) and 22.4m (22.4-NR), respectively. Four patients had G4 toxicity (anemia, febrile-neutropenia, severe neutropenia, sepsis), and 3 patients had G5 toxicity (thromboembolism, sepsis, colonic perforation). CONCLUSION: ABCPem was associated with increased PFS compared to historical controls but this difference did not meet the statistical significance. Three on-treatment deaths and 5 thromboembolic events prompted early closure.

Quantitative Reverse Transcription PCR Surveillance of SARS-CoV-2 Variants of Concern in Wastewater of Two Counties in Texas, United States.

After its emergence in late November/December 2019, the severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2) rapidly spread globally. Recognizing that this virus is shed in feces of individuals and that viral RNA is detectable in wastewater, testing for SARS-CoV-2 in sewage collections systems has allowed for the monitoring of a community's viral burden. Over a 9 month period, the influents of two regional wastewater treatment facilities were concurrently examined for wild-type SARS-CoV-2 along with variants B.1.1.7 and B.1.617.2 incorporated as they emerged. Epidemiological data including new confirmed COVID-19 cases and associated hospitalizations and fatalities were tabulated within each location. RNA from SARS-CoV-2 was detectable in 100% of the wastewater samples, while variant detection was more variable. Quantitative reverse transcription PCR (RT-qPCR) results align with clinical trends for COVID-19 cases, and increases in COVID-19 cases were positively related with increases in SARS-CoV-2 RNA load in wastewater, although the strength of this relationship was location specific. Our observations demonstrate that clinical and wastewater surveillance of SARS-CoV-2 wild type and constantly emerging variants of concern can be combined using RT-qPCR to characterize population infection dynamics. This may provide an early warning for at-risk communities and increases in COVID-19 related hospitalizations.

Integrating Metapopulation Dynamics into a Bayesian Network Relative Risk Model: Assessing Risk of Pesticides to Chinook Salmon (Oncorhynchus tshawytscha) in an Ecological Context.

The population level is often the biological endpoint addressed in ecological risk assessments (ERAs). However, ERAs tend to ignore the metapopulation structure, which precludes an understanding of how population viability is affected by multiple stressors (e.g., toxicants and environmental conditions) at large spatial scales. Here we integrate metapopulation model simulations into a regional-scale, multiple stressors risk assessment (Bayesian network relative risk model [BN-RRM]) of organophosphate (OP) exposure, water temperature, and DO impacts on Chinook salmon (Oncorhynchus tshawytscha). A matrix metapopulation model was developed for spring Chinook salmon in the Yakima River Basin (YRB), Washington, USA, including 3 locally adapted subpopulations and hatchery fish that interact with those subpopulations. Three metapopulation models (an exponential model, a ceiling density-dependent model, and an exponential model without dispersal) were integrated into the BN-RRM to evaluate the effects of population model assumptions on risk calculations. Risk was defined as the percent probability that the abundance of a subpopulation would decline from their initial abundance (500 000). This definition of risk reflects the Puget Sound Partnership's management goal of achieving "no net loss" of Chinook abundance. The BN-RRM model results for projection year 20 showed that risk (in % probability) from OPs and environmental stressors was higher for the wild subpopulations-the American River (50.9%-97.7%) and Naches (39.8%-84.4%) spring Chinook-than for the hatchery population (CESRF 18.5%-46.5%) and the Upper Yakima subpopulation (21.5%-68.7%). Metapopulation risk was higher in summer (58.1%-68.7%) than in winter (33.6%-53.2%), and this seasonal risk pattern was conserved at the subpopulation level. To reach the management goal in the American River spring Chinook subpopulation, the water temperature conditions in the Lower Yakima River would need to decrease. We demonstrate that 1) relative risk can vary across a metapopulation's spatial range, 2) dispersal among patches impacts subpopulation abundance and risk, and 3) local adaptation within a salmon metapopulation can profoundly impact subpopulation responses to equivalent stressors. Integr Environ Assess Manag 2021;17:95-109. © 2020 SETAC.

The structure of the death receptor 4-TNF-related apoptosis-inducing ligand (DR4-TRAIL) complex.

The structure of death receptor 4 (DR4) in complex with TNF-related apoptosis-inducing ligand (TRAIL) has been determined at 3 Šresolution and compared with those of previously determined DR5-TRAIL complexes. Consistent with the high sequence similarity between DR4 and DR5, the overall arrangement of the DR4-TRAIL complex does not differ substantially from that of the DR5-TRAIL complex. However, subtle differences are apparent. In addition, solution interaction studies were carried out that show differences in the thermodynamics of binding DR4 or DR5 with TRAIL.

Laboratory study of Hall reconnection in partially ionized plasmas.

The effects of partial ionization (n(i) / n(n) ≤ 1%) on magnetic reconnection in the Hall regime have been studied systematically in the Magnetic Reconnection Experiment. It is shown that, when neutrals are added, the Hall quadrupole field pattern and thus electron flow are unchanged while the ion outflow speed is reduced due to ion-neutral drag. However, in contrast to theoretical predictions, the ion diffusion layer width does not change appreciably. Therefore, the total ion outflow flux and the normalized reconnection rate are reduced.

Phase II 2-arm trial of the proteasome inhibitor, PS-341 (bortezomib) in combination with irinotecan or PS-341 alone followed by the addition of irinotecan at time of progression in patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck (E1304): a trial of the Eastern Cooperative Oncology Group.

BACKGROUND: Constitutive activation of nuclear factor κB (NF-κB) is associated with poor prognosis. Irinotecan demonstrates single-agent activity in head and neck cancer but activates NF-κB, promoting cell survival and resistance. Bortezomib is a proteasome inhibitor that inactivates NF-κB. PATIENTS AND METHODS: We performed a randomized phase II trial of bortezomib on days 1, 4, 8, and 11 and irinotecan on days 1 and 8 of each 21-day cycle or single-agent bortezomib on days 1, 4, 8, and 11 on a 21-day cycle. The addition of irinotecan to bortezomib was allowed in patients who progressed on bortezomib alone. RESULTS: The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with addition of irinotecan at time of progression on bortezomib. CONCLUSIONS: The bortezomib-based regimens evaluated in this study have minimal activity in recurrent or metastatic head and neck cancer.

Correlation of single leg vertical jump, single leg hop for distance, and single leg hop for time.

OBJECTIVES: To determine the correlation among three functional tests: single leg vertical jump (SLVJ), single leg hop for distance (SLHD), and single leg hop for time (SLHT). DESIGN: Prospective correlational investigation. SETTING: University research laboratory. PARTICIPANTS: Forty healthy men (n = 19) and women (n = 21) between the ages of 18 and 30 (23.9 ± 2.0 years). MAIN OUTCOME MEASURES: SLVJ was measured using the Vertec. SLHD was measured using a standard tape measure. SLHT was measured over a 10-m course using a standard stopwatch. RESULTS: The strongest correlation was between SLHT and SLHD, -0.89 and -0.89 for dominant and non-dominant lower extremities (LE), respectively. The weakest pairwise correlation was between SLVJ and SLHT, -0.71 and -0.63 for dominant and non-dominant LE, respectively. The correlation between SLVJ and SLHD was 0.74 and 0.71 for dominant and non-dominant LE, respectively. CONCLUSION: There is a strong correlation between SLHT and SLHD, suggesting that each test measures similar constructs of function, while the modest correlation between SLVJ and SLHT suggest these two tests do not measure the same functional components, and could be paired as outcome measures for the clinical assessment of lower extremity function.

Identification of a quasiseparatrix layer in a reconnecting laboratory magnetoplasma.

The concept of quasiseparatrix layers (QSLs) has emerged as a powerful tool to study the connectivity of magnetic field lines undergoing magnetic reconnection in solar flares. Although they have been used principally by the solar physics community until now, QSLs can be employed to shed light on all processes in which reconnection occurs. We present the first application of this theory to an experimental flux rope configuration. The three-dimensional data set acquired in this experiment makes the determination of the QSL possible.

Knockdown of m-calpain increases survival of primary hippocampal neurons following NMDA excitotoxicity.

The calpain family of cysteine proteases has a well-established causal role in neuronal cell death following acute brain injury. However, the relative contribution of calpain isoforms to the various forms of injury has not been determined as available calpain inhibitors are not isoform-specific. In this study, we evaluated the relative role of m-calpain and mu-calpain in a primary hippocampal neuron model of NMDA-mediated excitotoxicity. Baseline mRNA expression for the catalytic subunit of m-calpain (capn2 ) was found to be 50-fold higher than for the mu-calpain catalytic subunit (capn1) based on quantitative real-time PCR. Adeno-associated viral vectors designed to deliver short hairpin RNAs targeting capn1 or capn2 resulted in 60% and 90% knockdown of message respectively. Knockdown of capn2 but not capn1 increased neuronal survival after NMDA exposure at 21 days in vitro. Nuclear translocation of calpain substrates apoptosis inducing factor, p35/p25 and collapsin response mediator protein (CRMP) 2-4 was not detected after NMDA exposure in this model. However, nuclear translocation of CRMP-1 was observed and was prevented by capn2 knockdown. These findings provide insight into potential mechanisms of calpain-mediated neurodegeneration and have important implications for the development of isoform-specific calpain inhibitor therapy.

Neuroprotection with delayed initiation of prolonged hypothermia after in vitro transient global brain ischemia.

Prolonged therapeutic hypothermia (32-34 degrees C for 12-24 h) improves the functional outcome of comatose cardiac arrest survivors. It is generally believed that rapidly achieving target temperature optimizes neuroprotection. However, this hypothesis has not been tested systematically. In this study, we compared the neuroprotective effect of prolonged hypothermia initiated between 0 and 8 h after reoxygenation using an in vitro model of simulated global brain ischemia. Organotypic hippocampal slices were prepared from 5-day-old Wistar rat pups and cultured for 1 week prior to analysis. Ischemia was simulated by normothermic oxygen-glucose deprivation (OGD). Hypothermia (33 degrees C) was initiated 0-8 h after reoxygenation and maintained until 24 h post-injury. CA1 regional cell death was quantified by propidium iodide (PI) fluorescence. Release of 14-3-3 beta protein was evaluated as a potential surrogate maker for neuroprotection. Hypothermia initiated 0, 1, 2, or 4 h after 30 min OGD reduced 24 h CA1 regional PI fluorescence by 47 +/- 34%, 85 +/- 4%, 88 +/- 3%, and 88 +/- 5% (P < 0.05 for all versus normothermic reoxygenation). Direct comparison of hypothermia initiated 4 or 8 h after reoxygenation revealed equivalent neuroprotection following 15 and 30 min OGD, but neither was protective after 60 min OGD. Hypothermia initiated 4 or 8 h after 30 min OGD reduced 14-3-3 beta release by 73 +/- 11% and 92 +/- 4%, respectively (P < 0.01 for both versus normothermic reoxygenation). In this model, the neuroprotective effect of prolonged post-ischemic hypothermia is both optimal and equivalent when initiated between 1 and 8 h after reoxygenation. These results suggest the need for further in vivo studies to define the therapeutic window within which prolonged hypothermia is optimally neuroprotective after cardiac arrest.

Co-expression of alternatively spliced forms of PAX3, PAX7, PAX3-FKHR and PAX7-FKHR with distinct DNA binding and transactivation properties in rhabdomyosarcoma.

PAX3 and PAX7 encode transcription factors implicated in the pathogenesis of rhabdomyosarcoma (RMS), including alveolar RMS in which chromosomal translocations generate PAX3-FKHR and PAX7-FKHR fusions. Previous studies of wild-type PAX3 and PAX7 identified alternative splicing events that modify the paired box and generate 2 isoforms of PAX3 (Q+ and Q-) and 4 isoforms of PAX7 (Q+GL+, Q+GL-, Q-GL+, Q-GL-). In our study, we investigated alternative splicing of the wild-type and fusion forms of PAX3 and PAX7 in alveolar and embryonal RMS and assessed the functional implications. For PAX3 and PAX3-FKHR, the Q+ and Q- isoforms were consistently co-expressed in RMS tumors with slightly higher levels of the Q+ isoform. For PAX7 and PAX7-FKHR, there was a consistent pattern of co-expression of the 4 isoforms in RMS tumors: Q+GL- > Q+GL+ >/= Q-GL- > Q-GL+. DNA binding analysis demonstrated that PAX3 and PAX3-FKHR Q- isoforms exhibit higher affinity than corresponding Q+ isoforms for class I sites and no difference for class II sites. For PAX7 and PAX7-FKHR, the relative affinity was Q-GL- > Q+GL- > Q-GL+ >/= Q+GL+ for class I sites and Q-GL-, Q+GL- > Q-GL+, Q+GL+ for class II sites. Finally, the transcriptional activities of the PAX3-FKHR and PAX7-FKHR isoforms on reporter plasmids varied over a 5-fold and 50-fold range, respectively, in accord with the differences in DNA binding activity. In conclusion, these studies reveal that PAX3, PAX7 and their fusions with FKHR are each expressed in RMS tumors as a consistent mixture of functionally distinct isoforms.