Monitoring Deforestation in Rainforests Using Satellite Data: A Pilot Study from Kalimantan, Indonesia

Monitoring large forest areas is presently feasible with satellite remote sensing as opposed to time-consuming and expensive ground surveys as alternative. This study evaluated, for the first time, the potential of using freely available medium resolution (30 m) Landsat time series data for deforestation monitoring in tropical rainforests of Kalimantan, Indonesia, at sub-annual time scales. A simple, generic, data-driven algorithm for deforestation detection based on a consecutive anomalies criterion was proposed. An accuracy assessment in the spatial and the temporal domain was carried out using high-confidence reference sample pixels interpreted with the aid of multi-temporal very high spatial resolution image series. Results showed a promising spatial accuracy, when three consecutive anomalies were required to confirm a deforestation event. Recommendations in tuning the algorithm for different operational use cases were provided within the context of satisfying REDD+ requirements, depending on whether spatial accuracy or temporal accuracy need to be optimized

Architektur für ein System zur Dokumentanalyse im Unternehmenskontext - Integration von Datenbeständen, Aufbau- und Ablauforganisation

Workflowmanagementsysteme werden im Bürobereich verstärkt zur effizienten Geschäftsprozeßabwicklung eingesetzt. Das bereits Mitte der 70er Jahre propagierte papierlose Büro bleibt jedoch gegenwärtig immer noch Utopie. Dieser Widerspruch liegt darin begründet, daß die Handhabung von papierintensiven Vorgängen in hohem Maße abhängig ist von einer Identifkation und Aufbereitung der in den Dokumenten enthaltenen Informationen. Allerdings müssen solche Daten z.B. bei eingehender Post immer noch von Hand eingegeben werden. In diesem Dokument wird die Architektur eines System vorgestellt, das diesen Medienbruch überwinden soll. Techniken aus dem Gebiet der Dokumentanalyse und des Dokumentverstehens werden in den Workftowkontext integriert und nutzen das dort verfügbare Wissen zur Steigerung der Erkennungsqualität. Das Architekturdokument beruht auf einer ebenfalls dokumentierten Anforderungsanalyse (DFKI Dokument D-97-05). Es enthält eine statische und eine dynamische Beschreibung der benötigten Klassenkategorien und erklärt deren Funktionalität anhand eines umfassenden Beispiels

DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy

Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to beta-particle emitter Lutetium-177 labeled somatostatin analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of H2AX-foci formation and its downstream effects. To determine relative biological effectiveness (RBE) between the two isotopes somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks were quantified after immunofluorescence staining of H2AX. Cell cycle was analyzed by flow cytometry. In vivo, uptake of both radiolabeled somatostatin-analogues into subcutaneous AR42J tumors and number of cells displaying H2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities translated from in vitro cytotoxicity. Ac-225-DOTATOC was synthesized with specific activities between 0.2-0.4 MBq/µg and radiochemical purity of > 90%. ED50 values were 30 kBq/ml after 24 h and 14 kBq/ml after 48 h. Lu-177-DOTATOC displayed radiochemical purity of >95% and ED50 values of 10 MBq/ml after 48 h. Number of DNA double strand breaks increased with increasing concentration of Ac 225 DOTATOC and Lu-177-DOTATOC similarly, if a factor of approximately 700 of Lu-177 activities over Ac-225 activities was applied. Already 24 h after incubation with 2.5, 5, and 10 kBq/ml Ac 225 DOTATOC cell cycle studies showed an increment of the percentage of tumor cells in G2/M phase up to 60%. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical with 7.5 %ID/g, though overall number of cells with H2AX-foci was higher for tumors treated with 48 kBq Actinium-225-DOTATOC than tumors treated with 30 MBq Lutetium-177-DOTATOC (35% vs. 21%). Tumors with a mean volume of 0.34 ml reached exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC), after 21 days (34 MBq Lu-177-DOTATOC) and after 5 days (control). Thus H2AX-foci displayed the key parameter after irradiation with similar downstream effects for beta and alpha irradiation.JRC.E.5-Nuclear chemistr

Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells

Mitochondrial dsRNA; Cytosol; Inflammatory phenotypedsRNA mitocondrial; Citosol; Fenotipo inflamatoriodsRNA mitocondrial; Citosol; Fenotip inflamatoriThe escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.We are grateful to the IRB Functional Genomics Unit and CRG/CNAG for library preparation and genomic sequencing, to the IRB microscopy unit, and to the CCiUB flow cytometry facility for the technical support. We thank Ms. Tanya Liesel de Silva from the Gavathiotis lab for her technical assistance. V.L.P. was the recipient of a predoctoral contract from the Spanish Ministry of Education (FPU-18/05917). M.M. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement (No 794744), and from the Spanish Ministry of Science and Innovation (MCIN) (RYC2020-030652-I /AEI /10.13039/501100011033 and PID2022-142205OB-I00). E.Z., F.D.M.M. and E.G. were funded by the National Institutes of Health grants P01AG031782, P30AG038072, R01CA223243, and a Hevolution Foundation partnership grant. M.K. was funded by the Barcelona Institute of Science and Technology (BIST) and Asociación Española Contra el Cáncer (AECC; POSTD18020SERR), and supported by the European Molecular Biology Organization (EMBO). Work in the laboratory of M.S. was funded by the IRB and “laCaixa” Foundation, and by grants from the Spanish Ministry of Science co-funded by the European Regional Development Fund (ERDF) (SAF2017-82613-R), European Research Council (ERC-2014-AdG/669622), and Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282)

Molecular imaging and biochemical response assessment after a single cycle of [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy in mCRPC patients who have progressed on [177Lu]Lu-PSMA-617 monotherapy

Rationale: Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted 177Lu radioligand therapy in metastatic castration-resistant prostate carcinoma (mCRPC), some patients do not respond and other patients with initially good response develop resistance to this treatment. In this study, we investigated molecular imaging and biochemical responses after a single cycle of [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy in patients who had progressed on [177Lu]Lu-PSMA-617 monotherapy. Methods: Seventeen patients with mCRPC were included in a retrospective, monocenter study. Molecular imaging-based response was assessed by modified PERCIST criteria using the whole-body total lesion PSMA (TLP) and molecular tumour volume (MTV) derived from [68Ga]Ga-PSMA-11 PET/CT. Biochemical response was evaluated according to PCWG3 criteria using the prostate-specific antigen (PSA) serum value. Concordance and correlation statistics as well as survival analyses were performed. Results: Based on the molecular imaging-based response assessment, 5 (29.4%) patients showed partial remission and 7 (41.2%) had stable disease. The remaining 5 (29.4%) patients had further progression, four with an increase in TLP/MTV of >30% and one with stable TLP/MTV but appearance of new metastases. Based on the biochemical response assessment, 5 (29.4%), 8 (47.1%), and 4 (23.5%) patients showed partial remission, stable disease, and progressive disease, respectively. A comparison of the response assessment methods showed a concordance of 100% (17/17) between TLP and MTV and 70.6% (12/17) between TLP/MTV and PSA. Patients with partial remission, independently assessed by each method, had better overall survival (OS) than patients with either stable or progressive disease. The difference in OS was statistically significant for the molecular imaging response assessment (median OS not reached vs. 8.3 m, p = 0.044), but not for the biochemical response assessment (median OS 18.1 m vs. 9.4 m, p = 0.468). Conclusion: Based on both assessment methods, [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy is an effective treatment for the highly challenging cohort of patients with mCRPC who have progressed on [177Lu]Lu-PSMA-617 monotherapy. Molecular imaging response and biochemical PSA response were mostly concordant, though a considerable number of cases (29.4%) were discordant. Molecular imaging response reflecting the change in total viable tumour burden appears to be superior to PSA change in estimating survival outcome after tandem therapy

Renal Safety of [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Compromised Baseline Kidney Function

Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is an effective antitumor-treatment in metastatic castration-resistant prostate carcinoma (mCRPC). Concerns of potential nephrotoxicity are based on renal tubular PSMA expression and the resulting radiopharmaceutical retention during RLT, but data confirming clinically significant renal toxicity are still lacking. In this study, patients with significantly impaired baseline kidney function before initiation of therapy were investigated for treatment-associated nephrotoxicity and the potential relationship with administered activities of [177Lu]Lu-PSMA-617. Methods: Twenty-two mCRPC patients with impaired renal function (glomerular filtration rate (GFR) ≤ 60 mL/min) who received more than two cycles of [177Lu]Lu-PSMA-617 RLT (median 5 cycles and median 6-week time interval between consecutive cycles) were analyzed in this study. Patients were treated within a prospective patient registry (REALITY Study, NCT04833517). Cumulative administered activities ranged from 17.1 to 85.6 GBq with a median activity of 6.5 GBq per cycle. Renal function was closely monitored during and after PSMA-RLT. Results: Mean pre-treatment GFR was 45.0 ± 10.7 mL/min. After two (22/22 patients), four (20/22 patients), and six cycles (10/22 patients) of RLT, a significant increase of GFR was noted (each p < 0.05). End-of-treatment GFR (54.1 ± 16.7 mL/min) was significantly higher than baseline GFR (p = 0.016). Only one patient experienced deterioration of renal function (change of CTCAE grade 2 to 3). The remaining patients showed no significant reduction of GFR, including follow-up assessments (6, 9, and 12 months), and even showed improved (10/22 patients) or unchanged (11/22 patients) CTCAE-based renal impairment grades during and after the end of PSMA-RLT. No significant correlation between the change in GFR and per-cycle (p = 0.605) or cumulative (p = 0.132) administered activities were found. Conclusions: As pre-treatment chronic kidney failure did not lead to detectable RLT-induced deterioration of renal function in our study, the nephrotoxic potential of [177Lu]Lu-PSMA-617 RLT may be overestimated and not of clinical priority in the setting of palliative treatment in mCRPC. We suggest not to categorically exclude patients from enrolment to PSMA-RLT due to renal impairment

Addition of Standard Enzalutamide Medication Shows Synergistic Effects on Response to [177Lu]Lu-PSMA-617 Radioligand Therapy in mCRPC Patients with Imminent Treatment Failure—Preliminary Evidence of Pilot Experience

Well-received strong efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) does not prevent patients from either early or eventual disease progression under this treatment. In this study, we investigated co-medication with enzalutamide as a potential re-sensitizer for PSMA-RLT in patients with imminent treatment failure on standard 177Lu-based PSMA-RLT. Ten mCRPC patients who exhibited an insufficient response to conventional [177Lu]Lu PSMA-617 RLT received oral medication of enzalutamide 160 mg/d as an adjunct to continued PSMA RLT. Prostate-specific antigen (PSA) and standard toxicity screening lab work-up were performed to assess the treatment efficacy and safety in these individuals. The mean PSA increase under PSMA-RLT before starting the re-sensitizing procedure was 22.4 ± 26.5%. After the introduction of enzalutamide medication, all patients experienced a PSA decrease, –43.4 ± 20.0% and –48.2 ± 39.0%, after one and two cycles of enzalutamide-augmented PSMA-RLT, respectively. A total of 70% of patients (7/10) experienced partial remission, with a median best PSA response of –62%. Moreover, 5/6 enzalutamide-naïve patients and 2/4 patients who had previously failed enzalutamide exhibited a partial remission. There was no relevant enzalutamide-induced toxicity observed in this small cohort. This pilot experience suggests the synergistic potential of adding enzalutamide to PSMA-RLT derived from the intra-individual comparison of 177Lu-based PSMA-RLT ± enzalutamide

A Structure-Activity Relationship Study of Bimodal BODIPY-Labeled PSMA-Targeting Bioconjugates

The aim of this study was to identify a high-affinity BODIPY peptidomimetic that targets the prostate-specific membrane antigen (PSMA) as a potential bimodal imaging probe for prostate cancer. For the structure-activity study, several BODIPY (difluoroboron dipyrromethene) derivatives with varying spacers between the BODIPY dye and the PSMA Glu-CO-Lys binding motif were prepared. Corresponding affinities were determined by competitive binding assays in PSMA-positive LNCaP cells. One compound was identified with comparable affinity (IC50=21.5±0.1 nM) to Glu-CO-Lys-Ahx-HBED-CC (PSMA-11) (IC50=18.4±0.2 nM). Radiolabeling was achieved by Lewis-acid-mediated 19F/18F exchange in moderate molar activities (∼0.7 MBq nmol−1) and high radiochemical purities (>99 %) with mean radiochemical yields of 20–30 %. Cell internalization of the 18F-labeled high-affinity conjugate was demonstrated in LNCaP cells showing gradual increasing PSMA-mediated internalization over time. By fluorescence microscopy, localization of the high-affinity BODIPY-PSMA conjugate was found in the cell membrane at early time points and also in subcellular compartments at later time points. In summary, a high-affinity BODIPY-PSMA conjugate has been identified as a suitable candidate for the development of PSMA-specific dual-imaging agents

Response Assessment and Prediction of Progression-Free Survival by 68Ga-PSMA-11 PET/CT Based on Tumor-to-Liver Ratio (TLR) in Patients with mCRPC Undergoing 177Lu-PSMA-617 Radioligand Therapy

At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with 177Lutetium (177LuPSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and biochemical response assessments, and their potential prediction of progression-free survival (PFS). Fifty-one consecutive patients given two cycles of RLT at 6-week intervals were analyzed retrospectively. 68Ga-PSMA-11 PET/CT was obtained about 2 weeks prior to the first and 4–6 weeks after the second cycle. Molecular imaging-based response using SUVpeak and tumor-to-liver ratio (TLR) was determined by modified PERCIST criteria. ∆TLR and ∆SUV were significantly correlated with ∆PSA (p < 0.001, each). After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9–10.1) months. In univariate analysis, responders showing partial remission (PRPSA and PRTLR) had significantly (p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months). Response assessment using SUVpeak failed to predict survival. In multivariable analysis, response assessment using TLR was independently associated with PFS (p < 0.001), as was good performance status (p = 0.002). Molecular imaging-based response assessment with 68Ga-PSMA11 PET/CT using normalization of the total lesion PSMA over healthy liver tissue uptake (TLR) could be an appropriate biomarker to monitor RLT in mCRPC patients and to predict progression-free survival (PFS) of this treatment modalit

Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

The use of 225Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with 177Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in 177Lu-naive mCRPC patients (n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [68Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [177Lu]Lu-PSMA-617 RLT, with at least one [225Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort