Methylene Blue has a potent antiviral activity against SARS-CoV-2 and H1N1 influenza virus in the absence of UV-activation in vitro.

Methylene blue is an FDA (Food and Drug Administration) and EMA (European Medicines Agency) approved drug with an excellent safety profile. It displays broad-spectrum virucidal activity in the presence of UV light and has been shown to be effective in inactivating various viruses in blood products prior to transfusions. In addition, its use has been validated for methemoglobinemia and malaria treatment. In this study, we first evaluated the virucidal activity of methylene blue against influenza virus H1N1 upon different incubation times and in the presence or absence of light activation, and then against SARS-CoV-2. We further assessed the therapeutic activity of methylene blue by administering it to cells previously infected with SARS-CoV-2. Finally, we examined the effect of co-administration of the drug together with immune serum. Our findings reveal that methylene blue displays virucidal preventive or therapeutic activity against influenza virus H1N1 and SARS-CoV-2 at low micromolar concentrations and in the absence of UV-activation. We also confirm that MB antiviral activity is based on several mechanisms of action as the extent of genomic RNA degradation is higher in presence of light and after long exposure. Our work supports the interest of testing methylene blue in clinical studies to confirm a preventive and/or therapeutic efficacy against both influenza virus H1N1 and SARS-CoV-2 infections

Magnetic Field Uniformity Across the GF 9-2 YSO, L1082C Dense Core, and GF 9 Filamentary Dark Cloud

The orientation of the magnetic field (B-field) in the filamentary dark cloud GF 9 was traced from the periphery of the cloud into the L1082C dense core that contains the low-mass, low-luminosity Class 0 young stellar object (YSO) GF 9-2 (IRAS 20503+6006). This was done using SOFIA HAWC+ dust thermal emission polarimetry (TEP) at 216 um in combination with Mimir near-infrared background starlight polarimetry (BSP) conducted at H-band (1.6 um) and K-band (2.2 um). These observations were augmented with published I-band (0.77 um) BSP and Planck 850 um TEP to probe B-field orientations with offset from the YSO in a range spanning 6000 AU to 3 pc. No strong B-field orientation change with offset was found, indicating remarkable uniformity of the B-field from the cloud edge to the YSO environs. This finding disagrees with weak-field models of cloud core and YSO formation. The continuity of inferred B-field orientations for both TEP and BSP probes is strong evidence that both are sampling a common B-field that uniformly threads the cloud, core, and YSO region. Bayesian analysis of Gaia DR2 stars matched to the Mimir BSP stars finds a distance to GF 9 of 270 +/- 10 pc. No strong wavelength dependence of B-field orientation angle was found, contrary to previous claims.Comment: 18 pages, 6 figures ApJ, accepte

Free-form lens model and mass estimation of the high redshift galaxy cluster ACT-CL J0102-4915, "El Gordo"

We examine the massive colliding cluster El Gordo, one of the most massive clusters at high redshift. We use a free-form lensing reconstruction method that avoids making assumptions about the mass distribution. We use data from the RELICS program and identify new multiply lensed system candidates. The new set of constraints and free-form method provides a new independent mass estimate of this intriguing colliding cluster. Our results are found to be consistent with earlier parametric models, indirectly confirming the assumptions made in earlier work. By fitting a double gNFW profile to the lens model, and extrapolating to the virial radius, we infer a total mass for the cluster of $M_{200c}=(1.08^{+0.65}_{-0.12})\times10^{15}$M$_{\odot}$. We estimate the uncertainty in the mass due to errors in the photometric redshifts, and discuss the uncertainty in the inferred virial mass due to the extrapolation from the lens model. We also find in our lens map a mass overdensity corresponding to the large cometary tail of hot gas, reinforcing its interpretation as a large tidal feature predicted by hydrodynamical simulations that mimic El Gordo. Finally, we discuss the observed relation between the plasma and the mass map, finding that the peak in the projected mass map may be associated with a large concentration of colder gas, exhibiting possible star formation. El Gordo is one of the first clusters that will be observed with JWST, which is expected to unveil new high redshift lensed galaxies around this interesting cluster, and provide a more accurate estimation of its mass.Comment: 19 pages, 10 figures. Updated figure

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. Patients and methods: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 μg/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. Results: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. Conclusions: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosup-pression should be accepted in order to obtain a high anti-tumor activity of this regimen and a potential improvement in surviva

Primary cervical malignant teratoma with a rib metastasis in an adult: Five-year survival after surgery and chemotherapy: A case report with a review of the literature

We report a case of a man presenting with a cervical malignant teratoma and a chondrosarcomatous rib metastasis. He was alive and free of recurrence five years and 10 months (= 70 months) after resection of the primary mass, followed by chemotherapy and subsequent resection of the rib tumor. This is the 35th patient reported in the literature and the first description in which an ‘adjuvant' or primary chemotherapy was used. Previous patients with a cervical malignant teratoma, reported after lethal outcome, had survivals of one to 22 months (median nine months). In all patients with a preoperative clinical impression of an aggressive, differentiated or undifferentiated malignancy, the definite diagnosis of teratoma could only be made histologically. By analogy to germ cell tumors, the prognosis of malignant teratoma might be improved if complete excision is combined with new, adjuvant chemotherapy protocols for germ cell tumors. Lessons learned from this case are placed in the context of germ cell tumors in general and of non-gonadal malignant teratomas in particula

Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer

Background The toxicity profile of prolonged infusions of paclitaxel in combination with cyclophosphamide in metastat-ic breast cancer has already been defined. The objective of this dose-finding study was to determine the maximum tolerable doses (MTDs) of shorter (three-hour) infusions of paclitaxel in combination with i.v. bolus cyclophosphamide in patients who had previously received a maximum of one chemotherapy for advanced breast carcinoma. The MTD of the same regimen with granulocyte colony-stimulating factor (G-CSF) support was then established. Patients and methods Eighty women with metastatic breast cancer received a total of 352 fully evaluable courses of therapy. The starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2 given every three weeks. At least three patients were treated at each dose level and if there were dose-limiting toxic effects during the first cycles three additional patients were entered. G-CSF support (5 ug/kg s.c.) was added to the second cycle if specific dose-limiting toxicities had occurred during the first cycle. The MTD was defined as the dose level at which more than two of six patients presented dose-limiting toxicities during the first cycle. Results Febrile neutropenia (n = 4) and severe thrombo-cytopenia (n - 1) defined the MTDs of paclitaxel as 200 mg/m2 and of cyclophosphamide as 2,000 mg/m2 with or without G-CSF in patients with and, respectively, without prior chemotherapy for advanced disease. Non-hematologic toxicity was moderate. Recommended doses were 200 mg/m2 of paclitaxel and 1,750 mg/m2 of cyclophosphamide with or without G-CSF in patients with and, respectively, without prior chemotherapy. The overall response rate was 25% and 50%, respectively, in patients with and without prior chemotherapy for metastatic disease. Complete remissions (9%) were reported only in patients without prior chemotherapy; antitumour activity in women with anthracycline-resistant disease, with an 8% response rate (95% CI: 1%-26%), was poor. Conclusion Paclitaxel at 200 mg/m2 and cyclophosphamide at 1,750 mg/m2 can be safely administered every three weeks to women with advanced breast cancer. The moderate antitumour activity observed with the schedule tested argues against its use as initial therapy for advanced breast cance

Saturable metabolism of continuous high-dose ifosfamide with Mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients

Background: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide/mesna ± GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. Patients and methods: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. Results: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosup-pression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). Conclusion: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studie