Space radiation measurements during the Artemis I lunar mission.

Space radiation is a notable hazard for long-duration human spaceflight1. Associated risks include cancer, cataracts, degenerative diseases2 and tissue reactions from large, acute exposures3. Space radiation originates from diverse sources, including galactic cosmic rays4, trapped-particle (Van Allen) belts5 and solar-particle events6. Previous radiation data are from the International Space Station and the Space Shuttle in low-Earth orbit protected by heavy shielding and Earth's magnetic field7,8 and lightly shielded interplanetary robotic probes such as Mars Science Laboratory and Lunar Reconnaissance Orbiter9,10. Limited data from the Apollo missions11-13 and ground measurements with substantial caveats are also available14. Here we report radiation measurements from the heavily shielded Orion spacecraft on the uncrewed Artemis I lunar mission. At differing shielding locations inside the vehicle, a fourfold difference in dose rates was observed during proton-belt passes that are similar to large, reference solar-particle events. Interplanetary cosmic-ray dose equivalent rates in Orion were as much as 60% lower than previous observations9. Furthermore, a change in orientation of the spacecraft during the proton-belt transit resulted in a reduction of radiation dose rates of around 50%. These measurements validate the Orion for future crewed exploration and inform future human spaceflight mission design.

HERA: A Timepix-based radiation detection system for Exploration-class space missions.

The Hybrid Electronic Radiation Assessor (HERA) system is a Timepix-based ionizing radiation detector built for NASA Exploration-class crewed missions. The HERA performs data analysis on-system and generates telemetry messages for ingestion, display, and relay by the spacecraft. Several iterations of the hardware have been flown aboard the International Space Station as payloads to test system operation and gain experience with the hardware in the space radiation environment. The HERA system and its payload operations are described, and data collected by the various HERA systems are presented.

The importance of time-resolved personal Dosimetry in space: The ISS Crew Active Dosimeter.

Monitoring space radiation is of vital importance for risk reduction strategies in human space exploration. Radiation protection programs on Earth and in space rely on personal and area radiation monitoring instruments. Crew worn radiation detectors are crucial for successful crew radiation protection programs since they measure what each crewmember experiences in different shielding configurations within the space habitable volume. The Space Radiation Analysis Group at NASA Johnson Space Center investigated several compact, low power, real-time instruments for personal dosimetry. Following these feasibility studies, the Crew Active Dosimeter (CAD) has been chosen as a replacement for the legacy crew passive radiation detectors. The CAD device, based on direct ion storage technology, was developed by Mirion Dosimetry Services to meet the specified NASA design requirements for the International Space Station (ISS) and Artemis programs. After a successful Technology demonstration on ISS, the CAD has been implemented for ISS Crew operations since 2020. The current paper provides an overview of the CAD development, ISS results and comparison with the ISS Radiation Assessment Detector (RAD) and the Radiation Environment Monitor 2 (REM2) instruments.

Hypoxia-induced SUMOylation of E3 ligase HAF determines specific activation of HIF2 in clear-cell renal cell carcinoma.

Clear-cell renal cell cancer (CRCC) is initiated typically by loss of the tumor-suppressor VHL, driving constitutive activation of hypoxia-inducible factor-1 (HIF1) and HIF2. However, whereas HIF1 has a tumor-suppressor role, HIF2 plays a distinct role in driving CRCC. In this study, we show that the HIF1α E3 ligase hypoxia-associated factor (HAF) complexes with HIF2α at DNA to promote HIF2-dependent transcription through a mechanism relying upon HAF SUMOylation. HAF SUMOylation was induced by hypoxia, whereas HAF-mediated HIF1α degradation was SUMOylation independent. HAF overexpression in mice increased CRCC growth and metastasis. Clinically, HAF overexpression was associated with poor prognosis. Taken together, our results show that HAF is a specific mediator of HIF2 activation that is critical for CRCC development and morbidity.

Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.

Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here, we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of hypoxia-inducible factor-1α (HIF-1α) by tumor hypoxia strongly activates secretion of the sonic hedgehog (SHH) ligand by cancer cells, which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and hedgehog signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. Our findings strengthen the rationale for testing HIF inhibitors and may therefore represent a novel therapeutic option for pancreatic cancer.

Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome.

BACKGROUND: Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting. METHODS: We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided. RESULTS: Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers. CONCLUSIONS: Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.

Long-term outcomes of laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y gastric bypass in the United States.

BACKGROUND: Although laparoscopic adjustable gastric banding (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB) are the most common bariatric procedures performed in the past decade, little is known about their long-term (>5 years) outcomes. METHODS: A retrospective outcome study investigated 148 consecutive patients from a single practice who underwent LAGB from November 2000 to March 2002. The group was matched with 175 consecutive patients who underwent LRYGB from June 2000 to March 2005. Follow-up data for 5 years or longer was available for 127 LAGB patients (86%) and 105 LRYGB patients (60%). RESULTS: After an initial 4 years of progressive weight loss, body mass index (BMI) loss stabilized at 5-7 years at approximately 15 kg/m(2) for the LRYGB patients and at about 9 kg/m(2) for the LAGB patients with band in place (P < 0.01). At 7 years, the excess weight loss (EWL) was 58.6% for LRYGB and 46.3% for LAGB with band in place (P < 0.01). By 7 years, 19 LAGB patients (15%) had had their bands removed, bringing the failure rate for LAGB (including patients with less than 25% EWL) to 48.3% versus 10.7% for LRYGB (P < 0.01). By 10 years, 29 (22.8%) of the bands had been removed, bringing the total LAGB failure rate to 51.1%. In 10 years, 67 LAGB (52.8%) and 43 LRYGB (41%) adverse events had occurred. However, over time, the LRYGB group experienced 9 (8.6%) serious, potentially life-threatening complications, whereas the LAGB group had none (P < 0.001). One procedure-related death occurred in the LRYGB group. CONCLUSIONS: Over the long term, LRYGB had an approximate reduction of 15 kg/m(2) BMI and 60% EWL, a significantly better outcome than LAGB patients experienced with band intact. The main issue with LAGB was its 50% failure rate in the long term, as defined by poor weight loss and percentage of band removal. Nevertheless, LAGB had a remarkably safe course, and it may therefore be considered for motivated and informed patients.