2 tablas, 3 figuras ; This work presents a methodology which exploits the underlying biochemical structure of bioprocesses to estimate concentrations in aerobic fermenters from oxygen measurements. Although a number of estimators have been proposed over the years in the literature, the methodology proposed in this work is able to operate in transient conditions while does not require the knowledge of the growth kinetics. In addition, it can be also applied to fermenters where the spatial distribution of the concentrations is relevant. In this case, we propose a systematic approach to optimally locate the sensors based on the use of reduced order models. This method allows the reconstruction of the oxygen concentrations from a limited number of sensors. Finally, the methodology proposed will be illustrated on a horizontal tubular reactor for the production of gluconicacid by free-growth of Aspergillus niger. ; Financial support received from the Spanish Government (MCyT Projects PPQ2001-3643 and DPI2004-07444-C04-03) and Xunta de Galicia (PGIDIT02-PXIC40209PN). ; Peer reviewed
7 páginas, 6 figuras, 1 tabla ; In this work, the dissipative nature of spatially distributed bioprocess systems is exploited to develop efficient state observers based on a low dimensional dynamic representation of the original set of partial differential equations. The approach we suggest combines standard observer design techniques for bioreactors with efficient model reduction methodologies based on projection of the original concentration fields on low dimensional subspaces capturing the slow dynamics of the process. Aspects related with the location of sensors and their influence on the ability to reconstruct concentration fields will also be considered. Finally, the different aspects of the methodology, as well as the efficiency of the resulting observers will be illustrated on a case study of industrial interest, namely a tubular bioreactor producing gluconic acid by Aspergillus Niger ; This paper includes results of the joint research project that is supported by the bilateral agreements between Bulgarian academy of sciences and Process Engineering Group IIMCSIC. The authors acknowledge financial support received from the Spanish Government (MCyT Projects PPQ2001- 3643) and Xunta de Galicia (PGIDIT02-PXIC40209PN). ; Peer reviewed
Background: Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. Methods: Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as "non-progressors" if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. Results: Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors' tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased TREG signatures in gene expression studies in baseline—post-bevacizumab—tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating TREGs in non-progressors. Conclusions: This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. Trial registration: (www.clinicaltrials.gov): NCT02802098. Registered on June 16, 2020. ; MQF is a recipient of the following grants: AES - PI16/00354 funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF) and B2017/BMD3733 (Immunothercan-CM) - Call for Coordinated Research Groups from Madrid Region - Madrid Regional Government - ERDF funds. SM is a recipient of the following grants: Spanish Ministerio de Economía y Competitividad (MINECO) (SAF2017-83732-R; AEI/FEDER, EU) and co-funded by Comunidad de Madrid (B2017/BMD3733; Immunothercan-CM). RC is a recipient RC is a recipient of the ISCIII grants PIE15/00068 and PI17/01865. The study was also funded by CRIS Contra el Cancer Foundation and Astra Zeneca Spain. Astra Zeneca Spain provided durvalumab
Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as "non-progressors" if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors' tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased TREG signatures in gene expression studies in baseline-post-bevacizumab-tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating TREGs in non-progressors. This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. (www.clinicaltrials.gov): NCT02802098 . Registered on June 16, 2020. ; MQF is a recipient of the following grants: AES - PI16/00354 funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF) and B2017/BMD3733 (Immunothercan-CM) -Call for Coordinated Research Groups from Madrid Region -Madrid Regional Government -ERDF funds. SM is a recipient of the following grants: Spanish Ministerio de Economia y Competitividad (MINECO) (SAF2017-83732-R; AEI/FEDER, EU) and co-funded by Comunidad de Madrid (B2017/BMD3733; Immunothercan-CM). RC is a recipient RC is a recipient of the ISCIII grants PIE15/00068 and PI17/01865. The study was also funded by CRIS Contra el Cancer Foundation and Astra Zeneca Spain. Astra Zeneca Spain provided durvalumab. ; Sí
