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Abstract Background It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma. Methods RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70+ tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs. Results In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70+ tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70+ tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner. Conclusions We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70+ cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged

Composites made of carbon-fiber-reinforced carbon (C/C or CFC) are high-performance materials with a wide range of properties, making them especially suitable for the design of thermally and mechanically highly stressed components. As the production process of these high-performance materials is currently still very expensive, new concepts for an economical manufacturing process are required. This paper focusses on an innovative approach that uses the polymer-based pultrusion process for shaping with a subsequent carbonization step to C/C. In this process, carbon fibers (CF) and a phenolic resin were used to manufacture a semi-finished product made of unidirectional (UD) carbon-fiber-reinforced plastic (CFRP) with a fiber volume content of 66%. The C/C composite shows dimensional stability and has a flexural strength of approx. 240 MPa and a flexural modulus of approx. of 135 GPa with an elongation of 1.8%.

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype–phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants. [ABSTRACT FROM AUTHOR]

This work investigates the material extrusion‐based additive manufacturing (AM) process chain of a pure alumina‐based oxide ceramic matrix composite, starting from material selection, large‐scale compounding to pellets, the AM process itself, debinding and sintering as well as microstructural and mechanical characterization. The compounded pellets have a volume share of 50% binder (polyvinyl butyral [PVB], polyethylene glycol [PEG], and stearic acid) and 50% alumina (Al2O3, alumina powder, and Nextel 610 alumina fibers) with an aimed fiber volume share of 40% after sintering. The material is compounded on an industrial scale with approximately 10 kg/h and the material extrusion‐based AM process reaches speeds of up to 1000 mm/s. A variation of the feed rate leads to a significant increase in surface roughness and an increase in mass of 30%, in thickness of 12% and in width of 25%. The flexural behavior in the four‐point‐bending test can be described by a fast first peak and reaching higher flexural strength after the first crack subsequent with averages of 23.8 ± 3.6 MPa below.1% elongation. The fracture surfaces show the expected failure mechanisms like pull‐out and crack deflection. The resulting fiber length in the printed samples is 140 µm in average. [ABSTRACT FROM AUTHOR]

Recognizing the importance of timely guidance regarding the rapidly evolving field of hepatitis C management, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) developed a web-based process for the expeditious formulation and dissemination of evidence-based recommendations. Launched in 2014, the hepatitis C virus (HCV) guidance website undergoes periodic updates as necessitated by availability of new therapeutic agents and/or research data. A major update was released electronically in September 2017, prompted primarily by approval of new direct-acting antiviral agents and expansion of the guidance's scope. This update summarizes the latest release of the HCV guidance and focuses on new or amended recommendations since the previous September 2015 print publication. The recommendations herein were developed by volunteer hepatology and infectious disease experts representing AASLD and IDSA and have been peer reviewed and approved by each society's governing board.

Photoacoustic (PA) signals are typically broadband in nature. The bandwidth of PA signals depends on the size distribution of the underlying chromophores. Typically, conventional ultrasound (US) transducers, designed for pulse-echo imaging, have limited bandwidth, which reduces their sensitivity to the broadband PA signal. The rejection of out-of-band signals impairs image reconstruction, leading to the loss of image details. Visualization of biological structures, in particular deep targets with a range of sizes requires large acquisition bandwidth. In this work, we combine PA data acquired with two conventional US array probes with complementary frequency bands in order to widen the bandwidth. However, the two conventional transducers also differ in sensitivity and combining the data results in misrepresentation of PA signal strengths. Therefore, in this article we report a novel PA-based method to calibrate the relative sensitivities of the transducers. The proposed method was applied in various scenarios, including imaging vascular structures in vivo. Results revealed that it is feasible to visualize targets varying widely in sizes while combining complementary information acquired with dual US transducers. In addition, the application of sensitivity compensation ratios avoids misrepresentation in the imaging scheme by accounting for sensitivity differences of both transducers during image acquisition.

Coherence phenomena arise from interference, or the addition, of wave-like amplitudes with fixed phase differences. Although coherence has been shown to yield transformative ways for improving function, advances have been confined to pristine matter and coherence was considered fragile. However, recent evidence of coherence in chemical and biological systems suggests that the phenomena are robust and can survive in the face of disorder and noise. Here we survey the state of recent discoveries, present viewpoints that suggest that coherence can be used in complex chemical systems, and discuss the role of coherence as a design element in realizing function.

We present Einstein coefficient spectra and a detailed-balance derivation of generalized Einstein relations between them that is based on the connection between spontaneous and stimulated emission. If two broadened levels or bands overlap in energy, transitions between them need not be purely absorptive or emissive. Consequently, spontaneous emission can occur in both transition directions, and four Einstein coefficient spectra replace the three Einstein coefficients for a line. At equilibrium, the four different spectra obey five pairwise relationships and one lineshape generates all four. These relationships are independent of molecular quantum statistics and predict the Stokes' shift between forward and reverse transitions required by equilibrium with blackbody radiation. For Boltzmann statistics, the relative strengths of forward and reverse transitions depend on the formal chemical potential difference between the initial and final bands, which becomes the standard chemical potential difference for ideal solutes. The formal chemical potential of a band replaces both the energy and degeneracy of a quantum level. Like the energies of quantum levels, the formal chemical potentials of bands obey the Rydberg-Ritz combination principle. Each stimulated Einstein coefficient spectrum gives a frequency-dependent transition cross-section. Transition cross-sections obey causality and a detailed-balance condition with spontaneous emission, but do not directly obey generalized Einstein relations. Even with an energetic width much less than the photon energy, a predominantly absorptive forward transition with an energetic width much greater than the thermal energy can have such an extreme Stokes' shift that its reverse transition cross-section becomes predominantly absorptive rather than emissive. [ABSTRACT FROM AUTHOR]