Modeling the influence of slurry concentration on Saccharomyces cerevisiae cake porosity and resistance during microfiltration

Filtration of an isotonic suspension of baker's yeast through a 0.45-μm membrane was studied at two different pressures, 40 and 80 kPa, for yeast concentrations ranging from 0.14 to 51 kg/m3 (dry weight). For a yeast volume fraction above 0.06 (∼21.8 kg/m3), the porosity of the yeast cake is less dependent on the suspension concentration. For highly diluted suspensions, the specific cake resistance approaches a minimum that depends on the filtration pressure. Correlation functions of cake porosity and specific cake resistance were obtained for the concentration range investigated showing that the Kozeny–Carman coefficient increases when the applied pressure increases. Both filtration pressure and slurry concentration can be process controlled. In the range of moderate yeast concentration, the filtrate flux may be increased by manipulating the filtration pressure and the slurry concentration, thereby improving the overall process efficiency. The complex behavior of yeast cakes at high slurry concentration can be described by a conventional model as long as part of yeast cells are assumed to form aggregates, which behave as single bigger particles. The aggregation effect may be accounted for using a binary mixture model.The authors acknowledge the grant given to Dr. Yelshin by Fundacao para a Ciencia e Tecnologia (FCT), without which this work would not be possible. The authors also acknowledge the FCT funding of the project POCTI/EQU/55837/2004, under which the present research was performed. This work is intended to render homage to Alexander Yelshin, a long-term partner who wrote several articles with the authors, who passed away suddenly, to our grief

Modelling diffusivity in porous polymeric membranes with an intermediate layer containing microbial cells

Three-layer systems (membrane – composite layer (cells + polymer) – membrane) are important in different biochemical applications. Models of latex layered-membranes were evaluated and compared with experimental data in order to predict the diffusivity of substrates in the composite layer containing living E.coli microbial cells. Diffusivity predictions are dependent on the presence or the absence of a ‘skin’ layer, on the degree of polymer particle coalescence and on the thickness of each layer. Simulations with layered models were made to identify the dominant mechanisms in the three-layer system. It was found that the layered system is sensitive to the latex coatings porosity when the composite layer occupies less than 50% of the total membrane system thickness. Whenever the control of polymer particle coalescence and of the layers (coating/composite layer) thickness may be achieved, multi-layer systems presenting a wide range of relative diffusion conductivities may be built for different types of living cells and for a wide variety of practical applications. The diffusivity of the latex layer is proportional to the square of latex porosity.Fundação para a Ciência e a Tecnologia (FCT); FEDER

Continuous gas processing without bubbles using thin liquid film bioreactors containing biocomposite biocatalysts

Continuous microbial gas processing without bubbles is possible with thin liquid film, plug flow bioreactors. We have demonstrated that power input can be minimized by using a falling liquid film operating under laminar wavy flow conditions (Re \u3c200) in contact with highly concentrated living, non-growing microbes stabilized in a porous biocomposite biocatalyst. This composite materials approach to continuous gas processing can dramatically increase mass transfer rates \u3e100 fold compared to bubble aeration, decrease process volume, significantly decrease gas-liquid mass transfer energy input, decrease water use, and increase secreted product concentration. We have shown that this approach can also increase microbial specific activity for some organisms compared to microbes suspended in liquid media. Paper-based biocomposite biocatalysts provide a rough hydrophilic surface resulting in uniform ~300 μm thick falling liquid films. Paper roughness enhances gas-liquid-microbe mass transfer. This mass transfer enhancement has been simulated using a finite element (FEM) CFD model. The paper structure also functions as a separation device - the secreted products are released into the falling liquid film and continuously removed from the reactor. We are investigating biocomposite biocatalyst design and stabilization using a 0.05 m2 prototype cylindrical paper falling film bioreactor (FFBR). This approach can be used for continuous gas processing with either non-photosynthetic or photosynthetic microorganisms. Current experimental model systems we are investigating include Clostridium ljungdahlii OTA1 for absorbing CO from syn-gas, Methylomycrobium alkaliphilum 20Z for absorbing CH4 in air, and Chlamydomonas renhardtii for CO2 emissions. Critical to biocomposite biocatalyst design are generation of nanoporous coating microstructure, microbe adhesion to paper during film formation (which may include engineering the surface of the microbes), surviving osmotic shock in coating formulations, as well as desiccation tolerance to drying and prolonged dry storage. Spatially correlated Raman microspectroscopy and hyperspectral imaging techniques have been developed as a non-destructive method to monitor the distribution of residual water surrounding and within the cells. The distribution of vitrified residual water may contribute to desiccation resistance. Other types of thin liquid film reactors, such as a spinning disk bioreactor (SDBR), that enhance mass transfer by reducing liquid film thickness to \u3c100 μm with wave induced turbulent flow using centrifugal force (1000 x g) can be used in the future to further intensify continuous gas processing rates using biocomposite biocatalysts

Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases.

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro. GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer

Germline Polymorphisms in MGMT Associated With Temozolomide-Related Myelotoxicity Risk in Patients With Glioblastoma Treated on NRG Oncology/RTOG 0825

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions: Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients

The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

QUESTION: Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? TARGET POPULATION: These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection. RECOMMENDATIONS: Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS + or - WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (\u3e3 cm) or for those causing significant mass effect (\u3e1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below

Endocrinologic, neurologic, and visual morbidity after treatment for craniopharyngioma

Craniopharyngiomas are locally aggressive tumors which typically are focused in the sellar and suprasellar region near a number of critical neural and vascular structures mediating endocrinologic, behavioral, and visual functions. The present study aims to summarize and compare the published literature regarding morbidity resulting from treatment of craniopharyngioma. We performed a comprehensive search of the published English language literature to identify studies publishing outcome data of patients undergoing surgery for craniopharyngioma. Comparisons of the rates of endocrine, vascular, neurological, and visual complications were performed using Pearson’s chi-squared test, and covariates of interest were fitted into a multivariate logistic regression model. In our data set, 540 patients underwent surgical resection of their tumor. 138 patients received biopsy alone followed by some form of radiotherapy. Mean overall follow-up for all patients in these studies was 54 ± 1.8 months. The overall rate of new endocrinopathy for all patients undergoing surgical resection of their mass was 37% (95% CI = 33–41). Patients receiving GTR had over 2.5 times the rate of developing at least one endocrinopathy compared to patients receiving STR alone or STR + XRT (52 vs. 19 vs. 20%, χ2P < 0.00001). On multivariate analysis, GTR conferred a significant increase in the risk of endocrinopathy compared to STR + XRT (OR = 3.45, 95% CI = 2.05–5.81, P < 0.00001), after controlling for study size and the presence of significant hypothalamic involvement. There was a statistical trend towards worse visual outcomes in patients receiving XRT after STR compared to GTR or STR alone (GTR = 3.5% vs. STR 2.1% vs. STR + XRT 6.4%, P = 0.11). Given the difficulty in obtaining class 1 data regarding the treatment of this tumor, this study can serve as an estimate of expected outcomes for these patients, and guide decision making until these data are available