CAR T Cell Therapy in Hematological Malignancies: Implications of the Tumor Microenvironment and Biomarkers on Efficacy and Toxicity

Chimeric antigen receptor (CAR) T cell therapy has ushered in a new era in cancer treatment. Remarkable outcomes have been demonstrated in patients with previously untreatable relapsed/refractory hematological malignancies. However, optimizing efficacy and reducing the risk of toxicities have posed major challenges, limiting the success of this therapy. The tumor microenvironment (TME) plays an important role in CAR T cell therapy’s effectiveness and the risk of toxicities. Increasing research studies have also identified various biomarkers that can predict its effectiveness and risk of toxicities. In this review, we discuss the various aspects of the TME and biomarkers that have been implicated thus far and discuss the role of creating scoring systems that can aid in further refining clinical applications of CAR T cell therapy and establishing a safe and efficacious personalised medicine for individuals.     

Blocking the PCNA/NKp44 Checkpoint to Stimulate NK Cell Responses to Multiple Myeloma

Simple SummaryMembrane-associated PCNA is expressed on the surface of human MM cell lines and primary MM cells. Mab 14-25-9 interacts with membrane-associated PCNA and blocks its binding to NK-expressed NKp44, thus activating NK function. We showed that mAb 14-25-9 can serve as an immune checkpoint blocker, enhancing the function of NK cells on target human MM cell lines and primary cells.AbstractMultiple Myeloma (MM) is a devastating malignancy that evades immune destruction using multiple mechanisms. The NKp44 receptor interacts with PCNA (Proliferating Cell Nuclear Antigen) and may inhibit NK cells’ functions. Here we studied in vitro the expression and function of PCNA on MM cells. First, we show that PCNA is present on the cell membrane of five out of six MM cell lines, using novel anti-PCNA mAb developed to recognize membrane-associated PCNA. Next, we stained primary bone marrow (BM) mononuclear cells from MM patients and showed significant staining of membrane-associated PCNA in the fraction of CD38⁺CD138⁺ BM cells that contain the MM cells. Importantly, blocking of the membrane PCNA on MM cells enhanced the activity of NK cells, including IFN-γ-secretion and degranulation. Our results highlight the possible blocking of the NKp44-PCNA immune checkpoint by the mAb 14-25-9 antibody to enhance NK cell responses against MM, providing a novel treatment option.     

k‐strong privacy for radio frequency identification authentication protocols based on physically unclonable functions

This paper examines Vaudenay's privacy model, which is one of the first and most complete privacy models that featured the notion of different privacy classes. We enhance this model by introducing two new generic adversary classes, k‐strong and k‐forward adversaries where the adversary is allowed to corrupt a tag at most k times. Moreover, we introduce an extended privacy definition that also covers all privacy classes of Vaudenay's model. In order to achieve highest privacy level, we study low cost primitives such as physically unclonable functions (PUFs). The common assumption of PUFs is that their physical structure is destroyed once tampered. This is an ideal assumption because the tamper resistance depends on the ability of the attacker and the quality of the PUF circuits. In this paper, we have weakened this assumption by introducing a new definition k‐resistant PUFs. k‐PUFs are tamper resistant against at most k attacks; that is, their physical structure remains still functional and correct until at most k^th physical attack. Furthermore, we prove that strong privacy can be achieved without public‐key cryptography using k PUF‐based authentication. We finally prove that our extended proposal achieves both reader authentication and k‐strong privacy. Copyright © 2014 John Wiley & Sons, Ltd.     

Pt nanoparticles synthesized with new surfactants: improvement in C1–C3 alcohol oxidation catalytic activity

Platinum electrocatalysts were prepared using PtCl₄ as a starting material and 1-decylamine, N,N-dimethyldecylamine, 1-dodecylamine, N,N-dimethyldodecylamine, 1-hexadecylamine, and 1-octadecylamine as surfactants. These surfactants were used for the first time in this synthesis to determine whether the primary and/or tertiary structure and/or chain length of the surfactants, affects the size and/or activity of the catalysts in C₁–C₃ alcohol electro-oxidation reactions. Electrochemical measurements (cyclic voltammetry and chronoamperometry) indicated that the highest electrocatalytic performance was observed for the Pt nanocatalysts that were stabilized by N,N-dimethyldecylamine, and this has a tertiary amine structure with a short chain length (R = C₁₀H₂₁). The high performance may be due to the high electrochemical surface area, Pt(0)/Pt(IV) ratio, %Pt utility, and roughness factor (R _f). X-ray photoelectron spectroscopy, X-ray diffraction, atomic force microscopy, and transmission electron microscopy were used to determine the parameters that affect the catalytic activities.     

Gas chromatographic-olfactometric characterization of aroma active compounds in sun-dried and vacuum-dried tarhana

The influence of drying methods on the aroma active volatiles of sun-dried tarhana (SDT) and vacuum-dried tarhana (VDT) were compared using headspace SPME, GC-O and GC-MS. Although vacuum drying reduced the total amount of volatiles as compared to SDT (total FID peak area), more aroma active material was retained with VDT (total olfactory peak area). Vacuum drying retained a greater number of aroma active components (41) whereas the sun-dried method retained only 23. Aldehydes were the largest single class of aroma compounds in both types of tarhana: 17 in VDT and 10 in SDT. Other differentiating aroma compounds include alcohols, terpenes, and phenols such as geraniol, terpinolene, and 4-vinylguaiacol among others. A total of 22 aroma active components were present in greater amounts in the VDT versus only four aroma compounds present in greater amounts in the SDT.     

Inactivation of Penicillum expansum in sour cherry juice, peach and apricot nectars by pulsed electric fields

Inhibitory effects of pulsed electric fields (PEF) on Penicillum expansum inoculated into sour cherry juice, apricot and peach nectars were determined based on germination tube elongation, spore germination rate, and light and scanning electron microscopy (SEM) observations in this study. After inoculation of juice/nectar samples with P. expansum spores at the level of 10(5)-10(6)cfu/mL, the samples were processed by bench scale PEF pulse generator as a function of differing electric field strengths (0, 13, 17, 20, 23, 27, 30 and 34kV/cm) and processing times (0, 62, 94, 123, 163, 198 and 218mus). Results revealed that with an increase in electric field strength and processing time, germination tube elongation and spore germination rate were completely inhibited. Light and SEM observations revealed considerable morphological alterations in fungal conidia such as cytoplasmic coagulation, vacuolations, shrinkage and protoplast leakage. PEF processing of juice/nectars was demonstrated to be effective in inactivating P. expansum. To our knowledge, this is the first study confirming the inhibitory effects of PEF on germination tube elongation and spore germination rate of P. expansum in fruit juice/nectars.     

In Vitro Determination of the Antifungal Activity of Artemisia campestris Essential Oil from Algeria

The chemical composition of the essential oil isolated from the aerial parts of Artemisia campestris from Algeria and its antifungal activity against 10 filamentous fungal strains were investigated. The A. campestris essential oil was obtained in a yield of 0.71% (v/w). The major constituents of the oil were α-pinene (18.65%), β-pinene (16.78%), β-myrcene (17.34%), and germacrene D (10.34%). Our study showed that A. campestris essential oil was a potent antifungal agent against some pathogenic fungal species. Fusarium graminearum was the most sensitive strain to A. campestris essential oil with minimal inhibitory concentration and minimal fungicidal concentration values of 1.25 µL/mL (v/v). The essential oil also exhibited a strong fungicidal activity against the tested fungi, except for Penicillium citrinum, P. viridicatum, and Aspergillus niger (MFC >20 µL/mL). Our findings suggested the application of A. campestris essential oil as a biofungicide in order to reduce the dependence on synthetic fungicides and ensure food safety and quality.     

Microwave synthesis of mesoporous Cu-Ce0.8Sm0.2O2−δ composite anode for low-temperature ceramic fuel cells

In recent year, new nanocomposite electrolytes materials have been developed for low-temperature ceramic fuel cells (CFCs). To further improve the performance of CFCs based on the nanocomposite electrolyte, compatible active anode with sufficient low polarizations is needed. To improve the performance of anode, i.e. to enlarge tripe phase boundaries (TPB), anode materials with both porous structure and phase homogeneity of metal and ceramic are preferred. In the present study, we developed a novel microwave-assisted template-, surfactant-free synthesis route for mesoporous CuO–Ce_0.8Sm_0.2O_2−δ composite anode by homogeneous precipitation of microspherical precursor in aqueous solutions followed by calcination. The composite anode sample was characterized by thermogravimetry analysis, X-ray diffraction, SEM, EDX, etc. The characterization results indicated that CuO–SDC composite anode with mesoporous structure was prepared and both SDC and CuO phases were homogenously distributed. Fuel cells have been constructed using as-prepared composite as anodes and lithiated NiO as cathode based on the SDC–carbonate nanocomposite electrolyte. Fuel cell performance tests indicated that the cell with mesoporous Cu–SDC anode had better performance than conventional Cu–SDC anode prepared by solid-state method.     

Thermal stability study of SDC/Na2CO3 nanocomposite electrolyte for low-temperature SOFCs

The novel core–shell nanostructured SDC/Na₂CO₃ composite has been demonstrated as a promising electrolyte material for low-temperature SOFCs. However, as a nanostructured material, stability might be doubted under elevated temperature due to their high surface energy. So in order to study the thermal stability of SDC/Na₂CO₃ nanocomposite, XRD, BET, SEM and TGA characterizations were carried on after annealing samples at various temperatures. Crystallite sizes, BET surface areas, and SEM results indicated that the SDC/Na₂CO₃ nanocomposite possesses better thermal stability on nanostructure than pure SDC till 700 °C. TGA analysis verified that Na₂CO₃ phase exists steadily in the SDC/Na₂CO₃ composite. The performance and durability of SOFCs based on SDC/Na₂CO₃ electrolyte were also investigated. The cell delivered a maximum power density of 0.78 W cm⁻² at 550 °C and a steady output of about 0.62 W cm⁻² over 12 h operation. The high performances together with notable thermal stability make the SDC/Na₂CO₃ nanocomposite as a potential electrolyte material for long-term SOFCs that operate at 500–600 °C.