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HIV-1 Gag protein is synthesized in the cytosol and is transported to the plasma membrane, where viral particle assembly and budding occur. Endosomes are alternative sites of Gag accumulation. However, the intracellular transport pathways and carriers for Gag have not been clarified. We show here that Syntaxin6 (Syx6), a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) involved in membrane fusion in post-Golgi networks, is a molecule responsible for Gag trafficking and also for tumor necrosis factor-α (TNFα) secretion and that Gag and TNFα are cotransported via Syx6-positive compartments/vesicles. Confocal and live-cell imaging revealed that Gag colocalized and cotrafficked with Syx6, a fraction of which localizes in early and recycling endosomes. Syx6 knockdown reduced HIV-1 particle production, with Gag distributed diffusely throughout the cytoplasm. Coimmunoprecipitation and pulldown show that Gag binds to Syx6, but not its SNARE partners or their assembly complexes, suggesting that Gag preferentially binds free Syx6. The Gag matrix domain and the Syx6 SNARE domain are responsible for the interaction and cotrafficking. In immune cells, Syx6 knockdown/knockout similarly impaired HIV-1 production. Interestingly, HIV-1 infection facilitated TNFα secretion, and this enhancement did not occur in Syx6-depleted cells. Confocal and live-cell imaging revealed that TNFα and Gag partially colocalized and were cotransported via Syx6-positive compartments/vesicles. Biochemical analyses indicate that TNFα directly binds the C-terminal domain of Syx6. Altogether, our data provide evidence that both Gag and TNFα make use of Syx6-mediated trafficking machinery and suggest that Gag expression does not inhibit but rather facilitates TNFα secretion in HIV-1 infection. [ABSTRACT FROM AUTHOR]

The solar wind energy input and dissipation in the magnetospheric–ionospheric systems of 17 supersubstorms (SSSs: SML < −2500 nT) triggered by interplanetary shocks during solar cycles 23 and 24 are studied in detail. The SSS events had durations ranging from ∼42 minutes to ∼6 hr, and SML intensities ranging from −2522 nT to −4143 nT. Shock compression greatly strengthens the upstream interplanetary magnetic field southward component (B s), and thus, through magnetic reconnection at the Earth's dayside magnetopause, greatly enhances the solar wind energy input into the magnetosphere and ionosphere during the SSS events studied. The additional solar wind magnetic reconnection energy input supplements the ∼1.5 hr precursor (growth-phase) energy input and both supply the necessary energy for the high-intensity, long-duration SSS events. Some of the solar wind energy is immediately deposited in the magnetosphere/ionosphere system, and some is stored in the magnetosphere/magnetotail system. During the SSS events, the major part of the solar wind input energy is dissipated into Joule heating (∼30%), with substantially less energy dissipation in auroral precipitation (∼3%) and ring current energy (∼2%). The remainder of the solar wind energy input is probably lost down the magnetotail. It is found that during the SSS events, the dayside Joule heating is comparable to that of the nightside Joule heating, giving a picture of the global energy dissipation in the magnetospheric/ionospheric system, not simply a nightside-sector substorm effect. Several cases are shown where an SSS is the only substorm that occurs during a magnetic storm, essentially equating the two phenomena for these cases. [ABSTRACT FROM AUTHOR]

The primary scientific goal of ICARUS (Investigation of Coronal AcceleRation and heating of solar wind Up to the Sun), a mother-daughter satellite mission, proposed in response to the ESA "Voyage 2050" Call, will be to determine how the magnetic field and plasma dynamics in the outer solar atmosphere give rise to the corona, the solar wind, and the entire heliosphere. Reaching this goal will be a Rosetta Stone step, with results that are broadly applicable within the fields of space plasma physics and astrophysics. Within ESA's Cosmic Vision roadmap, these science goals address Theme 2: "How does the Solar System work?" by investigating basic processes occurring "From the Sun to the edge of the Solar System". ICARUS will not only advance our understanding of the plasma environment around our Sun, but also of the numerous magnetically active stars with hot plasma coronae. ICARUS I will perform the first direct in situ measurements of electromagnetic fields, particle acceleration, wave activity, energy distribution, and flows directly in the regions in which the solar wind emerges from the coronal plasma. ICARUS I will have a perihelion altitude of 1 solar radius and will cross the region where the major energy deposition occurs. The polar orbit of ICARUS I will enable crossing the regions where both the fast and slow winds are generated. It will probe the local characteristics of the plasma and provide unique information about the physical processes involved in the creation of the solar wind. ICARUS II will observe this region using remote-sensing instruments, providing simultaneous, contextual information about regions crossed by ICARUS I and the solar atmosphere below as observed by solar telescopes. It will thus provide bridges for understanding the magnetic links between the heliosphere and the solar atmosphere. Such information is crucial to our understanding of the plasma physics and electrodynamics of the solar atmosphere. ICARUS II will also play a very important relay role, enabling the radio-link with ICARUS I. It will receive, collect, and store information transmitted from ICARUS I during its closest approach to the Sun. It will also perform preliminary data processing before transmitting it to Earth. Performing such unique in situ observations in the area where presumably hazardous solar energetic particles are energized, ICARUS will provide fundamental advances in our capabilities to monitor and forecast the space radiation environment. Therefore, the results from the ICARUS mission will be extremely crucial for future space explorations, especially for long-term crewed space missions. [ABSTRACT FROM AUTHOR]

A search for extremely slow (V sw < 300 km sâˆ'1) solar winds (ESSWs) at 1 au has been conducted using hourly average solar wind data from 1963 through 2021. 297 ESSW events were identified with an average duration of ∼2.0 ± 1.4 days. The lowest speed detected was 156 km sâˆ'1. Ten of the lowest-speed events were analyzed in detail. It was found that all 10 events were located at the ends of high-speed solar wind (HSSW) streams. The termination of the ESSWs was caused by high-density plasmas, either a corotating interaction region associated with the next HSSW stream or a heliospheric plasma sheet encounter. There was a greater occurrence of ESSW events in solar cycles 23 and 24 than in previous solar cycles. This phenomenon is associated with the much lower solar activity during these two cycles. The decrease in solar polar open magnetic fields was accompanied by an increase in low and midlatitude open magnetic fields. The ESSWs were accompanied by low interplanetary magnetic fields (4.4 ± 2.1 nT) and low negative interplanetary B z fields (âˆ'1.7 ± 1.5 nT), which led to extreme geomagnetic quiet: AE = 67 ± 78 nT and Dst = 2.2 ± 9.9 nT. We encourage magnetospheric researchers to use ESSW events to better understand the ground states of the magnetosphere and ionosphere. [ABSTRACT FROM AUTHOR]

Pheochromocytoma (PCC) is rare catecholamine-producing endocrine tumor that metastasizes in approximately 10% of cases. As a functional imaging of PCC, 123I-metaiodobenzylguanidine (MIBG) scintigraphy was established, and some cases of PCC exhibit negative accumulation on MIBG scintigraphy, indicating a high risk of metastasis. Additionally, germline genetic variants of PCC are evident in approximately 30% of cases, although the genotype-phenotype correlation in PCC, especially the association between genetic mutations and MIBG scintigraphy, remains unclear. A 33-year-old man was admitted to our hospital for further examination for hypertension. He was diagnosed with sporadic PCC, and left adrenalectomy was performed. The adrenal tumor was negative on MIBG scintigraphy. Histology of the tumor revealed a moderately differentiated PCC. Target gene testing revealed a mutation in RET (c.2071G > A). This mutation has been reported to be a tumor-developing gene involved in the pathogenesis of PCC. Moreover, the RET mutation is the only gene mutation reported in a previous study of PCC with negative results on MIBG scintigraphy, except for the SDHB gene mutation, which is a common mutation in metastatic PCC. Correctively, the present RET gene mutation may be associated to MIBG-scintigraphy negative PCC and its pathophysiology. Clinicians should follow such cases more cautiously in clinical practice. [ABSTRACT FROM AUTHOR]

Preclinical models revealed potential synergistic effects of programmed cell death-1 inhibitors and anti-vascular endothelial growth factor (VEGF) antibodies. Therefore, we investigated the use of nivolumab, bevacizumab, and paclitaxel triple therapy for metastatic breast cancer. This phase 2, multicentre, single-arm study (NEWBEAT) investigated the safety and efficacy of first-line nivolumab, paclitaxel, and bevacizumab in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer, regardless of programmed cell death-ligand 1 expression. The primary end-point was objective response rate. Key secondary end-points included progression-free survival, overall survival, and toxicities. A biomarker study evaluated tumour programmed cell death-ligand 1 expression and serum VEGF-A levels. Between February 2018 and October 2018, 57 patients were enrolled. An objective response rate was seen in 39/56 patients (70%, 95% confidence interval [CI]: 55.9–81.2%), meeting the primary end-point. The objective response rate was 74% in patients with hormone receptor-positive breast cancer versus 59% in patients with triple-negative breast cancer. The median progression-free survival and overall survival were 14.0 (95% CI 11.0–16.3) and 32.5 (95% CI 26.0–not evaluable) months, respectively (median follow-up: 29.5 months). Grade 3/4 adverse drug reactions occurred in 33 of 57 patients (58%). There were no grade 5 adverse events. Immune-related adverse events occurred in 43 of 57 patients (75%), with grade 3/4 events in eight patients (14%). Biomarker analysis showed that tumour programmed cell death-ligand 1 expression was not correlated with the efficacy of triple therapy. Efficacy outcomes were similar between the serum VEGF-high and VEGF-low groups. First-line nivolumab, bevacizumab, and paclitaxel therapy showed promising efficacy and manageable toxicity in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. • First clinical trial to report efficacy of nivolumab, bevacizumab, and paclitaxel. • Objective response rates were promising (74% in HR+HER2− and 59% in patients with triple-negative breast cancer). • The median progression-free survival and overall survival were 14.0 months and 32.5 months, respectively. • Tumour programmed cell death-ligand 1 expression was not correlated with the efficacy of triple therapy. • Efficacy and prognosis were similar between serum vascular endothelial growth factor-high and vascular endothelial growth factor-low groups. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) usually accompanies suppressed plasma renin activity (PRA) through a negative feedback mechanism. While some cases of PA with unsuppressed PRA were reported, there have been no studies about the characteristics of PA with unsuppressed PRA; thus, these characteristics were examined herein. Nine patients with unsuppressed PRA and 86 patients with suppressed PRA were examined. All patients underwent segmental adrenal venous sampling (sAVS) and adrenalectomy, and were pathologically confirmed to have cytochrome P450 11B2 (CYP11B2)-positive aldosterone-producing adenoma according to international histopathology consensus criteria. Unsuppressed and suppressed PRA were defined as PRA levels of > 1.0 and ≤ 1.0 ng/mL/hr, respectively, in multiple blood samples obtained in the resting position. The unsuppressed PRA group had higher morning cortisol levels (12.6 [8.5, 13.5] vs. 8.5 [7.1, 11.0] μg/dL, P = 0.03) and higher cortisol levels after a 1 mg dexamethasone suppression test (DST) (2.2 [1.6, 2.5] vs. 1.3 [1.0, 1.9] μ g/dL, P = 0.004) than the suppressed PRA group. The unsuppressed PRA group also showed higher aldosterone levels on the non-surgical side during sAVS (P = 0.02 before adrenocorticotropic hormone (ACTH) stimulation, P = 0.002 after ACTH stimulation), a higher intensity of CYP17 expression in the resected adrenal gland (P = 0.02), and a lower clinical complete success rate 1 year after surgery (P = 0.04) compared with those in the suppressed PRA group. These findings suggest that PA should not be ruled out by unsuppressed PRA among patients with hypertension, particularly when their cortisol levels remain unsuppressed in the 1 mg DST. Meanwhile, it should be acknowledged that patients with unsuppressed PRA have higher aldosterone levels on the non-surgical side, and a lower likelihood of postoperative complete clinical success is to be expected. [ABSTRACT FROM AUTHOR]

BACKGROUND: Fosnetupitant (FosNTP), an intravenous neurokinin 1 receptor antagonist, demonstrated a favorable safety profile with a potentially low risk of injection site reactions (ISRs) and promising antiemetic efficacy in patients receiving cisplatin‐based highly emetogenic chemotherapy in a previous phase 2 study. We conducted a randomized, double‐blind safety study to evaluate the safety profile of FosNTP, including ISRs, in patients receiving doxorubicin‐cyclophosphamide or epirubicin‐cyclophosphamide (AC/EC) chemotherapy. METHODS: Patients scheduled to receive AC/EC were randomized 1:1 to receive 235 mg of FosNTP or 150 mg of fosaprepitant (FosAPR), both in combination with 0.75 mg of intravenous palonosetron and 9.9 mg of dexamethasone on day 1. The stratification factors were age category (<55 vs ≥55 years) and study site. The primary end point was the incidence of treatment‐related adverse events (TRAEs) with FosNTP. RESULTS: Overall, 102 patients were randomized to FosNTP (n = 52) or FosAPR (n = 50), and all were treated with the study drug and evaluated for safety. The primary end point, the incidence of TRAEs, was similar with FosNTP (21.2%; 95% confidence interval [CI], 11.1%‐34.7%) and FosAPR (22.0%; 95% CI, 11.5%‐36.0%), with any‐cause ISRs observed in 5.8% and 26.0% of patients, respectively, and treatment‐related ISRs observed in 0% and 10.0%, respectively. The overall (0‐120 hour) complete response (defined as no emetic event and no rescue medication) rate, standardized by age category in the full analysis set, was 45.9% (23 of 51 patients) with FosNTP and 51.3% (25 of 49 patients) with FosAPR. CONCLUSIONS: FosNTP demonstrated a favorable safety profile with a very low risk of ISRs in the AC/EC setting. Fosnetupitant shows a favorable safety profile in patients receiving doxorubicin‐cyclophosphamide or epirubicin‐cyclophosphamide chemotherapy. As an intravenous neurokinin 1 receptor antagonist with a low risk of causing injection site reactions, fosnetupitant may be used for protecting patients with cancer from experiencing chemotherapy‐induced nausea and vomiting. [ABSTRACT FROM AUTHOR]

The near-Earth solar wind is in general super-Alfvénic and supermagnetosonic. Using all available near-Earth solar wind measurements between 1973 and 2020, we identified 30 intervals with sub-Alfvénic solar winds. The majority (83%) of the events occurred within interplanetary coronal mass ejection magnetic clouds (MCs)/driver gases. These MC sub-Alfvénic events are characterized by exceptionally low plasma densities (Nsw) of ∼0.04–1.20 cm−3, low temperatures (Tsw) of ∼0.08 × 105 K to 12.46 × 105 K, enhanced magnetic field intensities (B0) of ∼8.3–53.9 nT, and speeds (Vsw) of ∼328–949 km s−1. The resultant high Alfvén wave speeds (VA) ranged from ∼410 to 1471 km s−1. This is consistent with a mechanism of the MC expansions as they propagate radially outward, causing small pockets of sub-Alfvénic wind regions within the MCs. The remainder of the sub-Alfvénic intervals (17%) occurred within the extreme trailing portions of solar wind high-speed streams (HSSs). These HSS sub-Alfvénic winds had low Nsw of ∼0.04–0.97 cm−3, low Tsw of ∼0.06 × 105 K to 0.46 × 105 K, B0 of ∼6.3–18.2 nT, Vsw of ∼234–388 km s−1, and a VA range of ∼364–626 km s−1. This is consistent with a mechanism of solar wind super-radial expansions in the trailing HSS regions. During sub-Alfvénic solar wind intervals, Earth's bow shock nose exhibited rapid evanescence, and the estimated geocentric magnetopause distance increased by ∼33%–86%. The inner magnetosphere was more or less unaffected by the sub-Alfvénic solar winds. No significant impact was observed in the outer radiation belt relativistic electrons, and no geomagnetic storms or substorms were triggered during the sub-Alfvénic solar wind events. [ABSTRACT FROM AUTHOR]

Background: Pheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B.Case Presentation: A 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father's paraganglioma tissues. In silico analysis predicted the mutation as "disease causing." She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery.Conclusions: We detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Renal dysfunction might quickly progress in patients with type 2 diabetes mellitus, when accompanied by hypertension. However, whether primary aldosteronism (PA), which autonomously over‐secretes aldosterone, causes additional renal damage in patients with type 2 diabetes mellitus is unclear. We evaluated the impact of PA on renal function in patients with type 2 diabetes mellitus. Materials and Methods: A retrospective review of all patients with type 2 diabetes mellitus who visited Yokohama Rosai Hospital's (Yokohama Japan) outpatient department between April 2017 and March 2018 was carried out. Records of patients with PA who underwent PA treatment by adrenalectomy or mineralocorticoid receptor antagonists (PA group) and those without PA (non‐PA group) were extracted, and renal function was compared between the two groups. Untreated PA patients were excluded, as their renal function might be overestimated as a result of glomerular hyperfiltration. Results: There were 83 patients in the PA group and 1,580 patients in the non‐PA group. The PA group had significantly lower estimated glomerular filtration rates than the non‐PA group (66.3 [52.4–78.2] vs 70.5 [56.0–85.6] mL/min/1.73 m2, P = 0.047). Multiple regression analysis showed that PA was a factor for decreased estimated glomerular filtration rate, independent of age, sex, glycated hemoglobin, diuretic use and hypertension (P = 0.025). PA induced a 3.7‐mL/min/1.73 m2 (95% confidence interval 0.47–6.9) decrease in estimated glomerular filtration rate, equivalent to that induced by 4.4 years of aging. Conclusions: Our results show that in patients with type 2 diabetes mellitus, PA is an independent risk factor for renal dysfunction. To prevent the progression of renal failure, PA should not be overlooked. [ABSTRACT FROM AUTHOR]

Aims. The expression for the shock Mach number used by Ravishankar and Michalek (2020, A&A, 638, A42) is incorrect. We wish to provide a correct expression so they can redo their analyses. Methods. Coronal mass ejection (CME) shocks are fast magnetosonic shocks and not intermediate Alfvén shocks. We give the steps for calculating the shock normal, shock velocity, and, thus, the shock Mach number. We also mention that the shock properties, such as being quasi-perpendicular or quasi-parallel, are another important parameter for the shock acceleration of energetic particles. Results. We have corrected the errors existing in the Astronomy and Astrophysics literature concerning the mathematical expression for the Mach number for a CME shock. Hopefully, future authors will use the now-correct expression for the Mach number. Conclusions. The correct shock Mach number expression has been given to Ravishankar and Michalek. It is hoped that they will redo their calculations (including using other shock properties) to see if their 2020 conclusions still hold true or not. [ABSTRACT FROM AUTHOR]

Interplanetary coronal mass ejections (ICMEs), magnetic clouds (MCs), sheaths, corotating interaction regions (CIRs), solar wind high-speed streams (HSSs), fast forward shocks (FSs), reverse waves (RWs), stream interfaces, and heliospheric current sheet crossings detected upstream of the Earth and their geoeffectiveness are studied during 2017 September. The most intense geomagnetic storm (SYM-H peak = −146 nT) starting on September 7 had a three-step main phase. A compound interplanetary structure resulting from an FS encountering and compressing the upstream MC southward interplanetary magnetic fields (IMFs) caused the first two steps of the storm. A magnetospheric supersubstorm (SSS; SML peak = −3712 nT) led to the third and most intense step. An MC portion of an ICME created an intense storm (SYM-H peak = −115 nT) on September 8. A second SSS (SML peak = −2642 nT) occurred during the main phase of this storm. Intense geomagnetically induced currents (GICs) occurred during the SSSs. Two moderate magnetic storms with peak SYM-H indices of −65 and −74 nT occurring on September 13 and 27 were caused by sheath and CIR southward IMFs, respectively. Six FSs and their associated sheaths caused sudden impulses (SI+s) of magnitude ranging from +11 to +56 nT. The shocks/sheaths led to magnetospheric relativistic electron flux decreases. The RWs caused SI−s and substorm recoveries by reducing southward IMFs. The high-intensity long-duration continuous AE activities (HILDCAAs) caused by the HSSs were related to the increase/acceleration of relativistic electron fluxes. [ABSTRACT FROM AUTHOR]

The association of intra‐individual variability in insulin requirements with C‐reactive protein levels among acute phase patients remains unclear. This retrospective cohort study aimed to evaluate this association. Patients with type 2 diabetes undergoing surgery for lumbar spinal canal stenosis were included in the study. We analyzed 286 records of 49 patients using the linear mixed effects model. The model showed C‐reactive protein levels to be significantly associated with insulin requirements, with an effect size of 0.60 U/day for an elevation of 1 mg/dL. The effect size was increased in patients with higher hemoglobin A1c levels. Our findings imply that C‐reactive protein levels could be a useful clinical biomarker when blood glucose levels are controlled in acute phase patients. [ABSTRACT FROM AUTHOR]

Background: Cancer patients experience pain that has physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Opioids are used in treatment of pain in patients with various types of cancer. We previously showed that the catechol-O-methyltransferase (COMT) genotype is related to the plasma level of morphine and the required dose of morphine in an exploratory prospective study. The findings showed that a group of patients with a GG single nucleotide polymorphism (SNP) rs4680 in COMT required a significantly higher dose of morphine than a non-GG group. A biomarker for selection of opioids for cancer pain relief would be particularly useful clinically, and therefore we have planned a randomized comparative study of morphine and oxycodone, using the COMT rs4680 SNP as a biomarker. This study is aimed at verifying the assumption that patients in the GG group require an increased morphine dose for pain relief.Methods: The RELIEF study is a randomized, multi-institutional, open-label trial with a primary endpoint of the proportion of subjects requiring high-dose opioids, as calculated from the dose of a rescue preparation administered on day 0. Secondary endpoints include the Hospital Anxiety and Depression Scale, Short form McGill Pain Questionnaire-2, European Organization for Research and Treatment of Cancer QLQ-C15-PAL, Pain Catastrophizing Scale, and adverse events, Eligibility criteria are patients with advanced carcinoma with non-daily use of opioids in initial screening for registration; and cancer pain targeted for daily opioid treatment, NSAIDs or acetaminophen, NRS ≥3(average over 24 h), opioid-treatment naive within 30 h, no chemotherapy, radiotherapy, or bisphosphonate administration newly started within 2 weeks, and written informed consent at the time of second registration. Between November 2014 and June 2017, an estimated 110 patients from two sites in Japan were randomized (1:1) to morphine or oxycodone in GG and non-GG groups.Discussion: A method for selection of appropriate opioids in cancer patients is a high unmet medical need. This study was designed to evaluate the efficacy of different opioids in patients with cancer based on gene polymorphism, as the first potential multi-institutional registration trial to be conducted in cancer patients with pain.Trial Registration: UMIN000015579 Date of registration: 4 November 2014. It is updated once every six months, the latest update is 30 June 2017. Trial status. The enrollment started in November 2014. At the time of manuscript submission (July 2017), Three-quarters of patients have participated. We thus expect to complete the recruitment by March 2018. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and potent topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing, advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion.Methods: We did an open-label, dose-escalation and dose-expansion phase 1 trial at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years of age in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with HER2-positive breast cancer has been completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978.Findings: Between Aug 28, 2015, and Aug 10, 2018, 115 of 118 patients with HER2-positive breast cancer were treated with at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. Frequent grade 3 or worse treatment-emergent adverse events included anaemia (19 [17%] of 115) and decreased neutrophil (16 [14%]), white blood cell (ten [9%]), and platelet (nine [8%]) counts. At least one serious treatment-emergent adverse event occurred for 22 (19%) patients. Investigators reported 20 cases of interstitial lung disease, pneumonitis, or organising pneumonia, including one grade 3 event and two treatment-related deaths due to pneumonitis. One death unrelated to study treatment was due to progressive disease. 66 (59·5%; 95% CI 49·7-68·7) of 111 patients had a confirmed objective response.Interpretation: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in trastuzumab emtansine-pretreated patients with HER2-positive breast cancer. These results suggest that further development in phase 2 and 3 clinical trials for HER2-positive breast cancer is warranted.Funding: Daiichi Sankyo Co, Ltd. [ABSTRACT FROM AUTHOR]

In the present randomized study, we assessed the efficacy of ipragliflozin compared with sitagliptin in 124 Japanese patients with type 2 diabetes. Sodium‐glucose co‐transporter‐2 inhibitor‐naïve and incretin‐related agent‐naïve patients were randomly assigned to receive additional 50 mg ipragliflozin or sitagliptin. The primary endpoint was the proportion of participants with >0.5% decrease in glycated haemoglobin (HbA1c) without body weight gain at 12 weeks. For secondary endpoints, we measured several biomarkers related to metabolic changes. After 12 weeks, 53.9% of participants in the ipragliflozin and 42.9% in the sitagliptin group reached the primary endpoint (P = 0.32). Decreases in homeostatic model assessment of insulin resistance, body fat percentage and skeletal muscle mass index, and increases in free fatty acids, ketone body concentration and HDL cholesterol levels were greater in the ipragliflozin group. Increases in homeostatic model assessment of β‐cell function and decreases in proinsulin‐to‐insulin ratio were greater in the sitagliptin group. No serious adverse events occurred in either group. In conclusion, ipragliflozin had beneficial effects on fat reduction, insulin resistance and lipid metabolism, while sitagliptin had beneficial effects on β‐cell function. [ABSTRACT FROM AUTHOR]

The impact of a high-speed solar wind stream (HSS) on the topside near-equatorial ionosphere (Arecibo: 28.17°N, L = 1.3) is investigated for the first time. Although the HSS did not lead to any significant geomagnetic storm activity, the ionosphere over Arecibo became hotter and expanded significantly in altitude as compared to a non-HSS interval. The O+/H+ transition height hT increased by ~200 km in the daytime and by ~100 km at night. At the hT, the peak ionospheric electron and ion temperatures increased by ~200-500 K during day and by ~50-70 K at night. While the O+ ion concentration exhibited an overall enhancement, deep penetration of the H+ ions below hT are observed during the day. The noontime peak electron density was ~4 times higher during the HSS event compared to the non-HSS interval. We present three possible mechanisms to explain this topside ionospheric heating. [ABSTRACT FROM AUTHOR]

Background Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used in patients with type 2 diabetes. However, the pleiotropic effects of sitagliptin is not well understood. Objective To assess the clinical efficacy and safety of sitagliptin on atherosclerosis, β-cell function, and glycemic control in Japanese patients with type 2 diabetes. Methods A prospective observational study of 270 patients with type 2 diabetes mellitus was carried out. Patients (aged 64.3 [12.4] years, body mas index 25.2 [4.3]) with glycated hemoglobin >6.9% (52 mmol/mol) or fasting plasma glucose >130 mg/dL were treated with sitagliptin for 12 months. The primary end point was glycated hemoglobin level changes from baseline to 3 months. The secondary end points included changes in several biomarkers related to inflammation and β-cell function from baseline to 3 months, as well as changes in glycated hemoglobin level from baseline to 12 months. Results Glycated hemoglobin levels were significantly lower in patients treated with sitagliptin for 3 months than at baseline (8.1% [1.4%]–7.3% [1.2%]) (65 [16.9]–56 [13.1] mmol/mol]) ( P < 0.0001), which continued after 12 months (7.4% [1.3%]) (56 [15.2] mmol/mol) ( P < 0.0001). In addition, a marker of vascular-specific inflammation, pentraxin-3, and a marker of β-cell function (proinsulin/insulin ratio), respectively, were lower after treatment with sitagliptin for 3 months than at baseline (1.88 [0.78]–1.65 [0.63] ng/mL [ P = 0.0038] and 0.20 [0.14]–0.17 [0.11] [ P = 0.01], respectively). On the other hand, a biomarker reflecting whole body inflammation; that is, high-sensitivity C-reactive protein level, was unchanged. Adverse events occurred in 14 patients (5.18%). Conclusions Sitagliptin may have beneficial effects on vascular inflammation and β-cell function in Japanese patients with type 2 diabetes. Pentraxin-3 may be an early predictive marker for detecting the antiatherosclerotic effects of dipeptidyl peptidase-4. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus enterotoxins cause debilitating systemic inflammatory responses, but how they spread systemically and trigger inflammatory cascade is unclear. In this study, we showed in mice that after inhalation, Staphylococcus aureus enterotoxin A rapidly entered the bloodstream and induced T cells to orchestrate systemic recruitment of inflammatory monocytes and neutrophils. To study the mechanism used by specific T cells that mediate this process, a systems approach revealed inducible and noninducible pathways as potential targets. It was found that TNF caused neutrophil entry into the peripheral blood, whereas CD28 signaling, but not TNF, was needed for chemotaxis of inflammatory monocytes into blood and lymphoid tissue. However, both pathways triggered local recruitment of neutrophils into lymph nodes. Thus, our findings revealed a dual mechanism of monocyte and neutrophil recruitment by T cells relying on overlapping and nonoverlapping roles for the noninducible costimulatory receptor CD28 and the inflammatory cytokine TNF. During sepsis, there might be clinical value in inhibiting CD28 signaling to decrease T cell-mediated inflammation and recruitment of innate cells while retaining bioactive TNF to foster neutrophil circulation. [ABSTRACT FROM AUTHOR]

CD134- and CD137-primed CD8 T cells mount powerful effector responses upon recall, but even without recall these dualcostimulated T cells respond to signal 3 cytokines such as IL-12.We searched for alternative signal 3 receptor pathways and found the IL-1 family member IL-36R. Although IL-36 alone did not stimulate effector CD8 T cells, in combination with IL-12, or more surprisingly IL-2, it induced striking and rapid TCR-independent IFN-g synthesis. To understand how signal 3 responses functioned in dual-costimulated T cells we showed that IL-2 induced IL-36R gene expression in a JAK/STAT-dependent manner. These data help delineate a sequential stimulation process where IL-2 conditioning must precede IL-36 for IFN-g synthesis. Importantly, this responsive state was transient and functioned only in effector T cells capable of aerobic glycolysis. Specifically, as the effector T cells metabolized glucose and consumed O2, they also retained potential to respond through IL-36R. This suggests that T cells use innate receptor pathways such as the IL-36R/axis when programmed for aerobic glycolysis. To explore a function for IL-36R in vivo, we showed that dual costimulation therapy reduced B16 melanoma tumor growth while increasing IL-36R gene expression. In summary, cytokine therapy to eliminate tumors may target effector T cells, even outside of TCR specificity, as long as the effectors are in the correct metabolic state. [ABSTRACT FROM AUTHOR]

Abstract: Scientific knowledge is acquired in geophysics generally without the benefit of controlled experiments. In this paper, we discuss how scientific inference based on observations occurs in geophysical contexts. We develop a specific approach that uses approximate simultaneity of proposed cause and effect phenomena to infer causality. The approach applies equally well to effect phenomena that follow the cause with a known time delay. We find that, in general, establishing a causal relationship between two phenomena based on simultaneity requires knowledge of how often simultaneity of these phenomena occurs in the absence of causality. We then extend the discussion to using numerical simulations in the scientific inference process. Numerical simulations of physical processes, because they can simulate the values of observations, are often used to infer what physical processes are occurring in nature. We discuss agreement between model output and observations as a basis for inferring the physical processes underlying the observations. We find that an important factor to consider, which we here call the “confusion factor,” is how often it may occur that insufficient model representations of the physical processes nevertheless lead to agreement between model computations and observations. We suggest that models of intermediate or low complexity may have a significant role to play when using geophysical simulations to reach scientific conclusions. [ABSTRACT FROM AUTHOR]

We have explored the use of COSMIC data to provide valuable scientific information on the ionospheric impacts of energetic particle precipitation during geomagnetic storms. Ionospheric electron density in the E region, and hence ionospheric conductivity, is significantly altered by precipitating particles from the magnetosphere. This has global impacts on the thermosphere-ionosphere because of the important role of conductivity on high-latitude Joule heating. Two high-speed stream (HSS) and two coronal mass ejection (CME) storms are examined with the COSMIC data. We find clear correlation between geomagnetic activity and electron density retrievals from COSMIC. At nighttime local times, the number of profiles with maximum electron densities in the E layer (below 200 km altitude) is well correlated with geomagnetic activity. We interpret this to mean that electron density increases due to precipitation are captured by the COSMIC profiles. These "E-layer-dominant ionosphere" (ELDI) profiles have geomagnetic latitudes that are consistent with climatological models of the auroral location. For the two HSS storms that occurred in May of 2011 and 2012, a strong hemispheric asymmetry is observed, with nearly all the ELDI profiles found in the Southern, less sunlit, Hemisphere. Stronger aurora and precipitation have been observed before in winter hemispheres, but the degree of asymmetry deserves further study. For the two CME storms, occurring in July and November of 2012, large increases in the number of ELDI profiles are found starting in the storm's main phase but continuing for several days into the recovery phase. Analysis of the COSMIC profiles was extended to all local times for the July 2012 CME storm by relaxing the ELDI criterion and instead visually inspecting all profiles above 50- magnetic latitude for signatures of precipitation in the E region. For 9 days during the July 2012 period, we find a signature of precipitation occurs nearly uniformly in local time, although the magnitude of electron density increase may vary with local time. The latitudinal extent of the precipitation layers is generally consistent with auroral climatology. However, after the storm main phase on 14 July 2012 the precipitation tended to be somewhat more equatorward than the climatology (by about 5-10° latitude) and equatorward of the auroral boundary data acquired from the SSUSI sensor onboard the F18 DMSP satellite. We conclude that, if analyzed appropriately, high-latitude COSMIC profiles have the potential to contribute to our understanding of MI coupling processes and extend and improve existing models of the auroral region. [ABSTRACT FROM AUTHOR]

We examine particularly intense substorms (SML ⩽ -2500 nT), hereafter called "supersubstorms" or SSS events, to identify their nature and their magnetic storm dependences. It is found that these intense substorms are typically isolated events and are only loosely related to magnetic storms. SSS events can occur during super (Dst ⩽ -250 nT) and intense (-100 nT⩾Dst> -250) magnetic storms. SSS events can also occur during nonstorm (Dst ⩾ -50 nT) intervals. SSSs are important because the strongest ionospheric currents will flow during these events, potentially causing power outages on Earth. Several SSS examples are shown. SSS events appear to be externally triggered by small regions of very high density (∼30 to 50 cm-3/ solar wind plasma parcels (PPs) impinging upon the magnetosphere. Precursor southward interplanetary magnetic fields are detected prior to the PPs hitting the magnetosphere. Our hypothesis is that these southward fields input energy into the magnetosphere/magnetotail and the PPs trigger the release of the stored energy. [ABSTRACT FROM AUTHOR]

Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE) tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (α = 2 x 10-5). The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100). KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100). DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples. [ABSTRACT FROM AUTHOR]

Background:We evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, recommended dose for phase II (P2RD), and preliminary anticancer activity of a combination eribulin and S-1 therapeutic in metastatic breast cancer patients pretreated with anthracycline and taxane.Method:Patients aged 20-74 years were recruited. In level 1, patients received S-1 (65 mg m−2) from day 1 to 14, and eribulin (1.1 mg m−2) on day 1 and 8 in a 21-day cycle. In level 2, eribulin was increased to 1.4 mg m−2. In level 3, S-1 was increased to 80 mg m−2.Results:Twelve patients were enrolled into three cohorts. Planned dose escalation was completed, with one case exhibiting dose-limiting toxicity (grade 3 hypokalaemia) at level 3, without reaching the MTD. The P2RD was determined to be level 2 (eribulin 1.4 mg m−2 and S-1 65 mg m−2). The most common grade 3 or 4 toxicity was neutropenia (83.3%), followed by febrile neutropenia (25.0%). Five of eleven patients (41.7%) with measurable disease had a partial response. Pharmacokinetics were characterised by dose-dependent elimination and nonlinear exposure.Conclusion:Dose level 3 was not tolerated owing to febrile neutropenia development. Thus, intermediate dose level 2 was recommended for further evaluation. Preliminary antitumour activity warrants further investigation in this setting. [ABSTRACT FROM AUTHOR]

We have explored the use of COSMIC data to provide valuable scientific information on the ionospheric impacts of energetic particle precipitation during geomagnetic storms. Ionospheric electron density in the E region, and hence ionospheric conductivity, is significantly altered by precipitating particles from the magnetosphere. This has global impacts on the thermosphere-ionosphere because of the important role of conductivity on high latitude Joule heating. Two high-speed stream (HSS) and two coronal mass ejection (CME) storms are examined with the COSMIC data. We find clear correlation between geomagnetic activity and electron density retrievals from COSMIC. At night 10 time local times, the number of profiles with maximum electron densities in the E layer (below 200 km altitude) is well correlated with geomagnetic activity. We interpret this to mean that electron density increases due to precipitation are captured by the COSMIC profiles. These "E layer dominant ionosphere" (ELDI) profiles have geomagnetic latitudes that are consistent with climatological models of the auroral location. For the two HSS storms, that occurred in May of 2011 and 2012, a strong hemispheric asymmetry is observed, with nearly all the ELDI profiles found in the southern, less sunlit, hemisphere. Stronger aurora and precipitation have been observed before in winter hemispheres, but the degree of asymmetry deserves further study. For the two CME storms, occurring in July and November of 2012, large increases in the number of ELDI profiles are found starting in the storm's main phase but continuing for several days into the recovery phase. Analysis of the COSMIC profiles was extended to all local times for the July 2012 CME storm by relaxing the ELDI criterion and instead visually inspecting all profiles above 50° magnetic latitude for signatures of precipitation in the E region. For nine days during the July 2012 period, we find a signature of precipitation occurs nearly uniformly in local time, although the magnitude of electron density increase may vary with local time. The latitudinal extent of the precipitation layers is generally consistent with auroral climatology. However, after the storm main phase on 14 July 2012, the precipitation tended to be somewhat more equator ward than predicted by the climatology (by about 5-10° latitude). We conclude that, if analyzed appropriately, high latitude COSMIC profiles have the potential to contribute to our understanding of MI coupling processes and extend and improve existing models of the auroral region. [ABSTRACT FROM AUTHOR]

In the article, the authors present the case of a 67-year-old male with type 2 diabetes who was rushed to a hospital due to right lower gingival pain and high fever to discuss hypervirulent Klebsiella pneumoniae (hvKP) infection in elderly patient with diabetes mellitus. He was eventually diagnosed with invasive liver abscess syndrome due to hvKP and was treated with cefotaxime.

Abstract: A series of four geomagnetic storms (the minimum SYM-H~−148nT) occurred during the March 6–17, 2012 in the ascending phase of the solar cycle 24. This interval was selected by CAWSES II for its campaign. The GPS total electron content (TEC) database and JPL's Global Ionospheric Maps (GIM) were used to study vertical TEC (VTEC) for different local times and latitude ranges. The largest response to geomagnetic activity is shown in increases of the low-latitude dayside VTEC. Several GPS sites feature post-afternoon VTEC “bite-outs”. During Sudden Impulse (SI+) event on March 8th a peak daytime VTEC restores to about quiet-time values. It is shown that the TIMED/SABER zonal flux of nitric oxide (NO) infrared cooling radiation correlates well with auroral heating. A factor of ~5 cooling increase is noted in some storms. The cooling radiation intensifies in the auroral zone and spreads towards the equator. Effects of the storm appear at lower latitudes ~18.6h later. The column density ratio Σ[O/N2] is analyzed based on TIMED/GUVI measurements. Both increases (at low latitudes) and decreases (from auroral to middle latitudes) in the ratio occurs during the geomagnetic storms. We suggest that the column density ratio could be enhanced at low to middle latitudes on the dayside partially due to the superfountain effect (atomic oxygen uplift due to ion-neutral drag). It is suggested that decreases in the Σ[O/N2] ratio at high to middle-latitudes may be caused by high thermospheric temperatures. During SI+s, there is an increase in Σ[O/N2] ratio at auroral latitudes. [Copyright &y& Elsevier]

Magnetic field magnitude decreases (MDs) are observed in several regions of the interplanetary medium. In this paper, we characterize MDs observed by the Ulysses spacecraft instrumentation over the solar south pole by using magnetic field data to obtain the empirical size, magnetic field MD, and frequency of occurrence distribution functions. The interaction of energetic (100 keV to 2 MeV) protons with these MDs is investigated. Charged particle and MD interactions can be described by a geometrical model allowing the calculation of the guiding center shift after each interaction. Using the distribution functions for the MD characteristics, Monte Carlo simulations are used to obtain the cross-field diffusion coefficients as a function of particle kinetic energy. It is found that the protons under consideration cross-field diffuse at a rate of up to ≈11% of the Bohm rate. The same method used in this paper can be applied to other space regions where MDs are observed, once their local features are well known. [ABSTRACT FROM AUTHOR]

We study solar wind-ionosphere coupling through the late declining phase/solar minimum and geomagnetic minimum phases during the last solar cycle (SC23) - 2008 and 2009. This interval was characterized by sequences of high-speed solar wind streams (HSSs). The concomitant geomagnetic response was moderate geomagnetic storms and high-intensity, long-duration continuous auroral activity (HILDCAA) events. The JPL Global Ionospheric Map (GIM) software and the GPS total electron content (TEC) database were used to calculate the vertical TEC (VTEC) and estimate daily averaged values in separate latitude and local time ranges. Our results show distinct low- and midlatitude VTEC responses to HSSs during this interval, with the low-latitude daytime daily averaged values increasing by up to 33 TECU (annual average of ~20 TECU) near local noon (12:00 to 14:00 LT) in 2008. In 2009 during the minimum geomagnetic activity (MGA) interval, the response to HSSs was a maximum of ~30 TECU increases with a slightly lower average value than in 2008. There was a weak nighttime ionospheric response to the HSSs. A well-studied solar cycle declining phase interval, 10-22 October 2003, was analyzed for comparative purposes, with daytime lowlatitude VTEC peak values of up to ~58 TECU (event average of ~55 TECU). The ionospheric VTEC changes during 2008-2009 were similar but ~60% less intense on average. There is an evidence of correlations of filtered daily averaged VTEC data with Ap index and solar wind speed. We use the infrared NO and CO2 emission data obtained with SABER on TIMED as a proxy for the radiation balance of the thermosphere. It is shown that infrared emissions increase during HSS events possibly due to increased energy input into the auroral region associated with HILDCAAs. The 2008-2009 HSS intervals were ~85% less intense than the 2003 early declining phase event, with annual averages of daily infrared NO emission power of ~3.3 × 1010W and 2.7 × 1010W in 2008 and 2009, respectively. The roles of disturbance dynamos caused by high-latitude winds (due to particle precipitation and Joule heating in the auroral zones) and of prompt penetrating electric fields (PPEFs) in the solar wind-ionosphere coupling during these intervals are discussed. A correlation between geoeffective interplanetary electric field components and HSS intervals is shown. Both PPEF and disturbance dynamo mechanisms could play important roles in solar wind-ionosphere coupling during prolonged (up to days) external driving within HILDCAA intervals. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Storming the Bastille: the effect of electric fields on the ionospheric F-layer" in the 2010 issue.

Background Eribulin is a recently approved new therapeutic option for patients with metastatic breast cancer. According to several reports, eribulin has limited ability to cross the blood brain barrier. Recently, capecitabine and eribulin have been recognized as drugs with similar application for patients with advanced breast cancer. Although there have been several case reports describing the efficacy of capecitabine against brain metastases, no report of eribulin demonstrating efficacy for brain metastases exists today. Case presentation We describe a case of a 57-year-old Japanese woman who was diagnosed with breast cancer stage IV metastasized to multiple organs including liver and lung. After she received 3 regimens, she showed evidence of brain metastases, and whole brain radiation therapy was performed. Lapatinib and capecitabine was then administered as fourth-line chemotherapy, but the patient was hospitalized due to the exacerbation of interstitial pneumonitis and progression of brain and liver metastases. To control the systemic disease, eribulin was commenced as fifth-line chemotherapy. One month later, a significant response of brain metastases had been achieved, and this response has persisted for the last 4 months. We now describe a remarkable antitumor effect of eribulin against brain metastases from breast cancer. This case is the first report which indicates potential treatment of brain metastases using this medication. Conclusion This report suggests that eribulin treatment may be beneficial for breast cancer patients with brain metastases progressing after whole brain radiation therapy. However, further clinical studies are warranted to determine the clinical effect of eribulin in brain metastases. [ABSTRACT FROM AUTHOR]

Abstract: Comet 19P/Borrelly plasma waves associated with the ion pickup process are being studied for the first time. The compressive plasma waves (short, large-amplitude, magnetic structures, or SLAMS) have peak-to-background magnetic field magnitude amplitudes as large as ∼9–1. A new method of analysis has been developed to study the properties these compressive waves (and the bow shock) and is applied in this study. The bow shock at the time of the DS1 crossing was determined to be quasiparallel in nature with θ Bn ∼22°. Using this new technique and minimum variance analyses over single wave cycles, most of the waves were determined to be circularly polarized, but some were noted to have linear and sunglass polarizations. The waves propagated obliquely to the ambient magnetic field B 0, with over 75% of the cases with θ kB0>45°. The intrinsic wave polarization in the plasma frame was investigated by examining waves propagating obliquely to the solar wind direction, θ kx >75°, where x is the solar wind velocity vector. From this analysis, a mix of right-hand (RH) and left-hand (LH) polarization waves were found, with no particular order, either as a function of distance upstream or closeness to the bow shock. Most of the waves were detected when B 0 was oblique to V sw . The equal mix of RH and LH waves is not well explained by current theoretical models. It is possible that the Dubouloz and Scholer (1995) scenario could work for this cometary case if both RH and LH waves were generated by ring-beam distributions. [Copyright &y& Elsevier]

Foreign-accented speakers are generally regarded as less educated, less reliable and less interesting than native speakers and tend to be associated with cultural stereotypes of their country of origin. This discrimination against foreign accents has, however, been discussed mainly using accented English in English-speaking countries. This study investigates the attitudes of Japanese people towards foreign-accented Japanese and their difference depending on the area of their residency, which will provide a valuable comparison to previous studies on the attitude towards foreign accent. Two groups of participants, one living in a metropolitan area and the other in a rural area, listened to a short Japanese passage spoken by Japanese native speakers and non-native (native English) speakers, and evaluated what they thought of each speaker's likely personality, job and social status. The participants rated native speakers higher than non-native speakers in competence and integrity, and rated both types of speakers equally only in social attractiveness. The results show that despite some admiration of and respect for western culture in Japanese society, when their judgement is based on auditory speech, Japanese participants evaluate fluent native speakers of Japanese more favourably than foreign-accented speakers. [ABSTRACT FROM AUTHOR]

Observed scale sizes of mirror modes in planetary magnetosheaths tend to be equal or larger than those that correspond to the maximum growth rate of the mirror instability: 9 pp (proton gyroradius). These phenomena can be accounted for by introducing a diffusion process (Bohm) that shifts the spectra to lower wave numbers as the mode convects away from the source to the observation point. The theory is applied to data obtained in the magnetosheaths of Earth, Jupiter, Saturn, and the heliosheath, and shown to provide reasonable agreement to past spacecraft observations. Further observational tests of the theory are suggested. [ABSTRACT FROM AUTHOR]

We study the interplanetary features and concomitant geomagnetic activity of the two high-speed streams (HSSs) selected by the Whole Heliosphere Interval (WHI) campaign participants: 20 March to 16 April 2008 in Carrington rotation (CR) 2068. This interval was chosen to perform a comprehensive study of HSSs and their geoeffectiveness during this 'deep' solar minimum. The two HSSs within the interval were characterized by fast solar-wind speeds (peak values > 600 km s) containing large-amplitude Alfvénic fluctuations, as is typical of HSSs during normal solar minima. However, the interplanetary magnetic field (IMF) magnitude [ B] was exceptionally low (≈3 - 5 nT) during these HSSs, leading to lower than usual IMF B values. The first HSS (HSS1) had favorable IMF polarity for geomagnetic activity (negative during northern Spring). The average AE and Dst for the HSS1 proper (HSS1P) were + 258 nT and − 21 nT, respectively. The second HSS (HSS2) had a positive sector IMF polarity, one that is less favorable for geomagnetic activity. The AE and Dst index averages were + 188 nT and − 7 nT, both lower than corresponding numbers for the first event, as expected. The HSS1P geomagnetic activity is comparable to, and the HSS2P geomagnetic activity lower than, corresponding observations for the previous minimum (1996). Both events' geomagnetic activities are lower than HSS events previously studied in the declining phase (in 2003). In general, V was faster for the HSSs in 2008 compared to 1996. The southward IMF B was lower in the former. The product of these two parameters [ V and IMF B] comprises the solar-wind electric field, which is most directly associated with the energy input into the magnetosphere during the HSS intervals. Thus the combined effects led to the solar wind energy input in 2008 being slightly less than that in 1996. A detailed analysis of magnetic-field variances and Alfvénicity is performed to explore the characteristics of Alfvén waves (a central element in the geoeffectiveness of HSSs) during the WHI. The B variances in the proto-CIR (PCIR) were ≈ 30 nT and < 10 nT in the high speed streams proper. [ABSTRACT FROM AUTHOR]

Abstract: The seven CAWSES interplanetary fast forward shocks and their geomagnetic effects during 2004–2005 have been analyzed. It is found that the arrival time of the shocks at Earth can be estimated within an accuracy of ∼5min. Furthermore, AL decreases are found to occur within 10min of shock impingement on the magnetopause. It was also determined that there is a direct correlation between the interplanetary magnetic field southward directed (IMF B s ) prior to shock arrival and substorms triggered by the shocks. If the IMF is northward prior to shock arrival, the geomagnetic activity is present but is low. One interpretation of this result is that the preconditioning energy stored in the magnetotail leaks away rapidly. A correlation between substorm peak AL and shock strength (Mach number) has also been noted, which could imply that shock strength is important for the amount of energy released into the magnetosphere/ionosphere. [Copyright &y& Elsevier]

Abstract: We experimentally identify mirror mode (MM) structures in the Voyager 1 heliosheath data for the first time. This is done using the magnetic field data alone. The heliosheath MM structures are found to have the following characteristics: (1) quasiperiodic spacings with a typical scale size of ∼57 ρ p, (2) little or no angular changes across the structures (∼3° longitude and ∼3° latitude), and (3) a lack of sharp boundaries at the magnetic dip edges. It is demonstrated that the pickup of interstellar neutrals in the upstream region of the termination shock (TS) and quasiperpendicular TS plasma compression are the causes of MM instability during intervals when the IMF is nearly orthogonal to the solar wind flow direction. Concomitant additional injection of pickup ions (PUIs) throughout the heliosheath will lead to further MM amplification. MM structures in planetary magnetosheaths and interplanetary sheaths are discussed for comparative purposes. Multiple sources of free energy are often involved. [Copyright &y& Elsevier]

Minima in geomagnetic activity (MGA) at Earth at the ends of SC23 and SC22 have been identified. The two MGAs (called MGA23 and MGA22, respectively) were present in 2009 and 1997, delayed from the sunspot number minima in 2008 and 1996 by ∼1/2-1 years. Part of the solar and interplanetary causes of the MGAs were exceptionally low solar (and thus low interplanetary) magnetic fields. Another important factor in MGA23 was the disappearance of equatorial and low latitude coronal holes and the appearance of midlatitude coronal holes. The location of the holes relative to the ecliptic plane led to low solar wind speeds and low IMF (Bz) variances (σBz2) and normalized variances (σBz2/B02 ) at Earth, with concomitant reduced solar wind-magnetospheric energy coupling. One result was the lowest ap indices in the history of ap recording. The results presented here are used to comment on the possible solar and interplanetary causes of the low geomagnetic activity that occurred during the Maunder Minimum. [ABSTRACT FROM AUTHOR]

Abstract: We aimed at elucidating the roles of transforming growth factor (TGF)-β and Smad3 signaling in adipocyte differentiation (adipogenesis) and in the pathogenesis of obesity. TGF-β/Smad3 signaling in white adipose tissue (WAT) was determined in genetically obese (ob/ob) mice. The effect of TGF-β on adipogenesis was evaluated in mouse embryonic fibroblasts (MEF) isolated both from WT controls and Smad3 KO mice by Oil red-O staining and gene expression analysis. Phenotypic analyses of high-fat diet (HFD)-induced obesity in Smad3 KO mice compared to WT controls were performed. TGF-β/Smad3 signaling was elevated in WAT from ob/ob mice compared to the controls. TGF-β significantly inhibited adipogenesis in MEF, but the inhibitory effects of TGF-β on adipogenesis were partially abolished in MEF from Smad3 KO mice. TGF-β inhibited adipogenesis independent from the Wnt and β-catenin pathway. Smad3 KO mice were protected against HFD-induced insulin resistance. The size of adipocytes from Smad3 KO mice on the HFD was significantly smaller compared to the controls. In conclusion, the TGF-β/Smad3 signaling pathway plays key roles not only in adipogenesis but also in development of insulin resistance. [Copyright &y& Elsevier]

Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer. [Copyright &y& Elsevier]

Abstract: Two high speed stream (HSS) solar wind intervals (days 283–294 and 314–318, 2003, hereafter called Events 1 and 2) during the declining phase of solar cycle 23 have been examined in detail for their interplanetary characteristics and their resultant geomagnetic activity. Event 1 had an associated storm initial phase with peak Dst=+9nT. This was caused by a high plasma density heliospheric plasma sheet (HPS) which impacted the magnetosphere. The southward component of IMF Bz fluctuations in the corotating interaction regions (CIRs) of both Events 1 and 2 led to peak storm main phases of Dst=−85 and −62nT, respectively. The extended storm “recovery” phases were associated with ΔB/B o ∼1–2 Alfvénic fluctuations in the HSS proper. High-intensity, long-duration, continuous AE (HILDCAA) intervals were present, presumably due to the southward component of the Alfvén waves. The IMF Bx–Vx 4-h cross-correlation values were >0.8 in Event 2, and lower, >0.6, in Event 1. The difference in Alfvénicity between the two HSS events is not understood at present. The IMF Bz 10-min to 3-h variances and are highest during the CIRs. The normalized variances during the HSS proper are approximately the same as those for the CIRs. For Event 1, the 1-h IMF and are 5.0nT2 and 1.1×10−1, respectively. The IMF Bz-AE cross-correlation (c.c.) coefficients during the storm main phase of Event 1 and for 24-h of the HSS of Event 2 give similar results. For the Event 1, a peak c.c. of −0.4 occurred with a lag of 103min, and for Event 2 a peak c.c of −0.38 with a lag of 67min was obtained. Both c.c. results were sharply peaked. The decay-portion of a HSS prior to Event 1 was characterized by low Np, low B o and low Alfvén wave amplitudes. The 1-h IMF and were 0.84nT2 and 2.9×10−2, respectively. This quiet interplanetary interval led to a quiet geomagnetic activity period (AE<100nT, Dst ∼+5nT). On the other hand, what is quite surprising is that this region was the most purely “Alfvénic” interval studied (c.c. of Bx-Vx=0.95). The ε parameter was calculated using both GSE and GSM coordinates. It was found that ε is ∼30% larger for GSM coordinates. Thus, the major cause of geomagnetic activity during HSSs is the large amplitude Alfvén waves but not coordinate transformations. Sector polarities (IMF By values) may be a secondary factor. However, other models, like the tilted solar dipole, should be considered as well. [Copyright &y& Elsevier]

Abstract: Interplanetary discontinuities and their geomagnetic effects are reviewed for magnetospheric/space weather researchers. Discontinuities are particularly useful as diagnostics since they are clearly identifiable in interplanetary data and their geomagnetic effects are unambiguous most of the time. Directional discontinuities (DDs) are abrupt changes in the interplanetary magnetic field direction and plasma parameters. DDs may be rotational discontinuities (RDs), tangential discontinuities (TDs) contact discontinuities (CDs) or shocks (fast (FS), intermediate (IS) and slow (SS). Shocks can propagate in the direction of the driver (forward shocks or FSs) or opposite to the driver (reverse shocks of RSs). Discontinuities interacting with other discontinuities may create new discontinuities. Fast forward shocks (FFSs) are shown to energize trapped particles by compressive effects, cause dayside aurora, lead to the creation of new radiation belts and to trigger nightside sector magnetospheric substorms. Fast reverse shocks (FRSs) or reverse waves (RWs) lead to magnetospheric expansions and the cessation of geomagnetic activity. TD-bow shock interactions create hot flow anomalies (HFAs) which then lead to outward expansions of the local magnetopause and dayside auroral enhancements. Some DD crossings may cause sudden southward IMF turnings. These cause magnetic reconnection and energy input into the magnetosphere–ionosphere–magnetotail system. Substorms sometimes occur thereafter. DDs that entail northward IMF turnings may lead to the triggering of substorms. [ABSTRACT FROM AUTHOR]

Abstract: In this article, we study fast shocks at CIR boundaries during an extended interval of 15 consecutive major high speed solar wind streams in 1992–1993. Ulysses was 4–5AU from the sun. The Abraham-Schrauner shock normal method and the Rankine-Hugoniot relations were used to determine fast shock directions and speeds. Out of 33 potential CIR shocks, 14 were determined to be fast forward shocks (FSs) and 14 were fast reverse shocks (RSs). Of the remaining 5 events, 2 were forward waves and 3 were reverse waves. CIR edges at latitudes below ∼30o were, for the most part, bounded by fast magnetosonic shocks. The forward shocks were generally quasi-perpendicular (average θnBo =67o). The reverse shocks were more oblique (average θnBo =52o), but they extended to all angles. Both FSs and RSs had magnetosonic Mach numbers ranging from 1 to 5 or 6. The average Mach numbers were 2.4 and 2.6 for FSs and RSs, respectively. The shock Mach numbers were noted to generally decrease with increasing latitude. The non-shock events or waves were noted to occur preferentially at high (∼−30° to −35°) heliolatitudes where stream-stream interactions were presumably weaker. These results are consistent with expectations, indicating the general accuracy of the Abraham-Schrauner technique. [Copyright &y& Elsevier]