[Allogeneic CAR-T for treatment of relapsed and/or refractory multiple myeloma: four cases report and literatures review].

Objective: To investigate the safety and efficacy of allogeneic CAR-T cells in the treatment of relapsed/refractory multiple myeloma (RRMM) . Methods: CAR-T cells were prepared from peripheral blood lymphocytes of HLA mismatch healthy donors. Median age was 55 (48-60) . Allogeneic cells were derived from 3 HLA haploidentical donors and 1 HLA completely mismatch unrelated donor. Four patients with RRMM were conditioned with FC regimen followed by CAR-T cell transfusion. They were infused into CART-19 (1×10(7)/kg on day 0) and (4.0-6.8) ×10(7)/kg CART-BCMA cells as split-dose infusions (40% on day 1 and 60% on day 2) . The adverse reactions and clinical efficacy were observed during follow-up after infusion, and the amplification and duration of CAR-T cells in vivo were monitored by PCR technique. Results: CAR-T cells were successfully infused in 3 of the 4 RRMM patients according to the study plan, and the infusion in one patient was delayed by 1 day due to high fever and elevated creatinine levels on day 3. The side effects included hematological and non-hematological toxicity, grade 3 hematological toxicity in 2 patients, grade 3 CRS in 1 one, grade 1 CRES in 1 one, prolonged APTT in 3 ones, tumor lysis syndrome in 1 one, mixed chimerism detected STR and clinical GVHD manifestation in 1 one. According to the efficacy criterias of IMWG, 2 patients acquired PR, 1 MR, and 1 SD respectively. Progression-free survival was 4 (3-5) weeks and overall survival was 63 (3-81) weeks. CAR T cells were amplified 2.2 (2-14) times in the patients with a median survival time of 10 (8-36) days. Conclusions: Small sample studies suggested that GVHD may be present in the treatment of RRMM with allogeneic CAR-T cells. There were early clinical transient events after transfusion. Low amplification and short duration of CAR-T cells in vivo may be the main factors affecting the efficacy.

Predictors of whole-body vibration levels among urban taxi drivers.

To identify a set of important WBV predictors that could be used to develop a statistical instrument for exposure assessment in a large epidemiologic study, a total of 432 WBV measures were taken from a sample of 247 male drivers in Taipei City, Taiwan. In accordance with the ISO 2631-1 (1997) methods, we measured the frequency-weighted vertical acceleration (z-axis) over drivers' seat surface, under conditions representing different types of rides (vacant vs. short vs. long) assigned to random destinations. Mixed effect models were used to analyse the WBV data including repeated measures. For this group of urban taxi drivers regularly exposed to WBV of low intensity (mean = 0.31 ms( - 2), ranging from 0.17 to 0.55 ms( - 2) r.m.s.), our analyses indicated that average driving speed was the primary predictor (p < 0.0001). As average driving speed increased, measured vertical acceleration increased in a quadratic-linear manner (p < 0.0001). Other WBV predictors, after adjusting for the effects of other covariates, included automobile manufacturer (p = 0.02), engine size (p = 0.04), body weight (p = 0.002), age (p = 0.02), use of seat cushion (p = 0.03), and traffic period (p = 0.02). Our study suggests that a similar statistical approach could be employed in future studies to improve the quality and efficiency of WBV exposure assessment in professional drivers.

Direct-method-aided phasing of MIR diffraction data from proteins.

Direct methods have successfully been used to break the phase ambiguity intrinsic in the single isomorphous replacement (SIR) data of proteins. Based on this, the procedure 'direct-method-aided MIR phasing' (DMIR) has been proposed and applied to the four-derivative multiple isomorphous replacement (MIR) data of a known protein containing 682 amino acid residuals in the asymmetric unit. The data set consists of 14,500 unique reflections at 3 A resolution with F(obs.) greater than 2sigma. Test calculation showed that the phases from conventional MIR phasing could be significantly improved by direct methods leading to obvious improvement in the quality of the resultant Fourier maps.

The slip resistance of common footwear materials measured with two slipmeters.

The slip resistance of 16 commonly used footwear materials was measured with the Brungraber Mark II and the English XL on 3 floor surfaces under surface conditions of dry, wet, oily and oily wet. Three samples were used for each material combination and surface condition. The results of a one way ANOVA analysis indicated that the differences among different samples were statistically significant for a large number of material combinations and surface conditions. The results indicated that the ranking of materials based on their slip resistance values depends highly on the slipmeters, floor surfaces and surface conditions. For contaminated surfaces including wet, oily and oily wet surfaces, the slip resistance obtained with the English XL was usually higher than that measured with the Brungraber Mark II. The correlation coefficients between the slip resistance obtained with these two slipmeters calculated for different surface conditions indicated a strong correlation with statistical significance.

Overexpression, purification, crystallization and preliminary crystallographic studies on a thermostable beta-glycosidase from Thermus nonproteolyticus HG102.

A thermostable beta-glycosidase (Tn-gly) from Thermus nonproteolyticus HG102 has been cloned and overexpressed in Escherichia coli. The recombinant enzyme, with a molecular mass of 48.9 kDa, was purified to homogeneity. It can hydrolyze a wide range of oligosaccharides and perform transglycosylation. Crystals of the recombinant enzyme were grown by the hanging-drop vapour-diffusion technique with MPD and NaCl as precipitants. They belong to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 66.7, b = 94.6, c = 176.5 A.

Crystal structure of R-phycocyanin and possible energy transfer pathways in the phycobilisome.

The crystal structure of R-phycocyanin from Polysiphonia urceolata (R-PC-PU) at 2.4 A is reported. The R-PC-PU crystal belongs to space group P4(3)2(1)2 with cell parameters a = 135.1 A, c = 210.0 A, and alpha = beta = gamma = 90 degrees. The structure was determined by molecular replacement. The crystallographic R-factor of the refined model is 0.189 (R(free) = 0.239). Comparison of the microenvironment of chromophore beta 155 in R-PC-PU and in C-PC from Fremyolla diphosiphon (C-PC-FD) reveals that their spectral differences may be caused by their different alpha 28 residues. In the R-PC-PU crystal structure, two (alpha beta)(3) trimers assemble face to face to form a hexamer, and two such hexamers assemble in two novel side-to-side arrangements. Possible models for the energy transfer from phycoerythrin to phycocyanin and from phycocyanin to allophycocyanin are proposed based on several phycobiliprotein crystal structures.

Structure of C-phycocyanin from Spirulina platensis at 2.2 A resolution: a novel monoclinic crystal form for phycobiliproteins in phycobilisomes.

The crystal structure of C-phycocyanin from the cyanobacterium S. platensis has been determined at 2.2 A resolution. The crystals belong to the monoclinic crystal form, which has not been previously reported for phycobiliprotein structures. The structure was solved using the molecular-replacement method with a final R value of 18.9% (R(free) = 23.7%) after model building and refinement. In the crystals used for the study, the C-phycocyanin hexamers formed by face-to-face association of two trimers are arranged in layers rather than in columns. Three different kinds of packing between adjacent hexamers in the layer were compared. The tight packing of two adjacent hexamers formed by four trimers in the asymmetric unit brings beta155 PCB chromophores close together, so it is possible that lateral energy transfer takes place through the beta155-beta155 route.

The effect of surface roughness and contaminant on the dynamic friction of porcelain tile.

Surface roughness affects friction, but it is not clear what surface roughness characteristics are better correlated with friction. The average of the maximum height above the mean line in each cut-off length (Rpm) and the arithmetical average of surface slope (deltaa) had the highest correlation with dynamic friction coefficient in a previous study. The previous study was expanded to two different footwear materials and four different contaminants on a porcelain tile in the current investigation. The results showed that dynamic friction decreased as the interface speed and glycerol content in the contaminant were increased due to the hydrodynamic lubrication effect. Deltaa had the highest correlation with friction for most of the test conditions with neolite. For Four S rubber, friction coefficient appeared to have the highest correlation with the parameters related to the surface void volume at 30% glycerol content, related to the surface slope at 70 and 85% glycerol contents, and related to the peak to valley distance at 99% glycerol content. A good indicator of surface slip resistance probably should consist of the surface parameters representing the surface slope, the surface void volume and the surface peak-to-valley distance with the coefficients determined by the system parameters.

The measurement of slipperiness--an international scientific symposium.

Occupational slips, trips, and falls (STF) present a tremendous burden on the working people of the world. The precise contribution of slipping to this burden is not completely understood and significant questions exist regarding the definition and measurement of slipperiness. In an attempt to advance slipperiness measurement, a workshop symposium of tribologists, biomechanists, clinicians, engineers, epidemiologists and related scientists was held in order to summarize the state of the science in slipperiness measurement. Organized into issue-focused working groups, participants collaborated on manuscripts addressing conceptual and definitional issues, the contribution of slipperiness to STF injury, and biomechanical, human-centred, and tribological approaches to slipperiness measurement. The conference design, contributions of working groups and outcomes are summarized.

Measurement of slipperiness: fundamental concepts and definitions.

The main objective of this paper is to give an overview of basic concepts and definitions of terms related to the 'measurement of slipperiness' from the onset of a foot slide to a gradual loss of balance and a fall. Other unforeseen events prior to falls (e.g. tripping) are sparingly dealt with. The measurement of slipperiness may simply comprise an estimation of slipping hazard exposures that initiate the chain of events ultimately causing an injury. However, there is also a need to consider the human capacity to anticipate slipperiness and adapt to unsafe environments for avoiding a loss of balance and an injury. Biomechanical and human-centred measurements may be utilized for such an approach, including an evaluation of relevant safety criteria for slip/fall avoidance and procedures for validation of slip test devices. Mechanical slip testing approaches have been readily utilized to measure slipperiness in terms of friction or slip resistance but with conflicting outcomes. An improved understanding of the measurement of slipperiness paradigm seems to involve an integration of the methodologies used in several disciplines, among others, injury epidemiology, psychophysics, biomechanics, motor control, materials science and tribology.

The role of surface roughness in the measurement of slipperiness.

Surface roughness has been shown to have substantial effects on the slip resistance between shoe heels and floor surfaces under various types of walking environments. This paper summarizes comprehensive views of the current understanding on the roles of surface roughness on the shoe and floor surfaces in the measurement of slipperiness and discusses promising directions for future research. Various techniques and instruments for surface roughness measurements and related roughness parameters are reviewed in depth. It is suggested that a stylus-type profilometer and a laser scanning confocal microscope are the preferred instruments for surface roughness measurements in the field and laboratory, respectively. The need for developing enhanced methods for reliably characterizing the slip resistance properties is highlighted. This could be based on the principal understanding of the nature of shoe and floor interface and surface analysis techniques for characterizing both surfaces of shoe and floor. Therefore, surface roughness on both shoe and floor surfaces should be measured and combined to arrive at the final assessment of slipperiness. While controversies around the friction measurement for slipperiness assessment still remain, surface roughness measurement may provide an objective alternative to overcoming the limitations of friction measurements.

The role of friction in the measurement of slipperiness, Part 1: friction mechanisms and definition of test conditions.

Friction has been widely used as a measure of slipperiness. However, controversies around friction measurements remain. The purposes of this paper are to summarize understanding about friction measurement related to slipperiness assessment of shoe and floor interface and to define test conditions based on biomechanical observations. In addition, friction mechanisms at shoe and floor interface on dry, liquid and solid contaminated, and on icy surfaces are discussed. It is concluded that static friction measurement, by the traditional use of a drag-type device, is only suitable for dry and clean surfaces, and dynamic and transition friction methods are needed to properly estimate the potential risk on contaminated surfaces. Furthermore, at least some of the conditions at the shoe/floor interface during actual slip accidents should be replicated as test conditions for friction measurements, such as sliding speed, contact pressure and normal force build-up rate.

The role of friction in the measurement of slipperiness, Part 2: survey of friction measurement devices.

This paper seeks to address questions related to friction measurement such as how friction is related to human-centred assessment and actual slipping, and how repeatable friction measurements are. Commonly used devices for slipperiness measurement are surveyed and their characteristics compared with suggested test conditions from biomechanical observations summarized in Part 1. The issues of device validity, repeatability, reproducibility and usability are examined from the published literature. Friction assessment using the mechanical measurement devices described appears generally valid and reliable. However, the validity of most devices could be improved by bringing them within the range of human slipping conditions observed in biomechanical studies. Future studies should clearly describe the performance limitations of any device and its results and should consider whether the device conditions reflect these actual human slipping conditions. There is also a need for validation studies of more devices by walking experiments.

Purification, crystallization and preliminary crystallographic studies on the N-terminal fragment of human protein disulfide isomerase.

A fragment of human protein disulfide isomerase composed of the thioredoxin-like a and b domains (ab) has been expressed in Escherichia coli as a fusion protein with glutathione-S-transferase and purified after thrombin cleavage. Two forms of ab crystal were obtained with polyethylene glycol as precipitant and different additives at pH 7.5. The space group of form I is P4(1)2(1)2 or P4(3)2(1)2, with unit-cell dimensions a = 81.5, c = 259.7 A. The space group of form II is P4(1)22 or P4(3)22, with unit-cell dimensions a = 82.7, c = 86.5 A.

The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold.

The first structure of an aldehyde dehydrogenase (ALDH) is described at 2.6 A resolution. Each subunit of the dimeric enzyme contains an NAD-binding domain, a catalytic domain and a bridging domain. At the interface of these domains is a 15 A long funnel-shaped passage with a 6 x 12 A opening leading to a putative catalytic pocket. A new mode of NAD binding, which differs substantially from the classic beta-alpha-beta binding mode associated with the 'Rossmann fold', is observed which we term the beta-alpha,beta mode. Sequence comparisons of the class 3 ALDH with other ALDHs indicate a similar polypeptide fold, novel NAD-binding mode and catalytic site for this family. A mechanism for enzymatic specificity and activity is postulated.

Crystal structure of desheptapeptide(B24-B30)insulin at 1.6 A resolution: implications for receptor binding.

The crystal structure of desheptapeptide (B24-B30) insulin (DHPI), a virtually inactive analog of insulin, was determined at 1.6 A resolution. In the refined structure model, DHPI retains three alpha-helices (A1-A8, A12-A18, and B9-B19) as its structural framework, while great conformational changes occur in the N and C termini of B-chain. The beta-turn, which lies in B20-B30 in insulin and insulin analogs with high potency, no longer exists in DHPI. Relative motion is observed among the three alpha-helices, each as a rigid functional group. In contrast, a region covering B5-B6 and A6-A11 exhibits a relatively stable conformation. We interpret our results as identifying: (i) the importance of beta-turn in determining the receptor-binding potency of insulin and (ii) a leading role of PheB24 in maintaining the beta-turn structure.

Structure of monomeric porcine DesB1-B2 despentapeptide (B26-B30) insulin at 1.65 A resolution.

Insulin has a concentration of 10(-8)-10(-11) M in the blood which ensures that it circulates and exerts its physiological functions in vivo as a monomer. The crystal structure of monomeric porcine desB1-B2 despentapeptide (B26-B30) insulin (DesB1-2 DPI) with M(r) = 4934 Da has been determined at 1.65 A resolution using the molecular replacement method. A structural comparison between DesB1-2 DPI and 2Zn insulin reveals that the conformation of DesB1-2 DPI is more similar to molecule I than molecule II of 2Zn insulin. The remarkable conformational difference between B25-Phe in DesB1-2 DPI and B25-Phe in despentapeptide (B26-B30) insulin (DPI) indicates that the residue B25-Phe possesses great flexibility and mobility.

Crystal structure of R-phycoerythrin from Polysiphonia urceolata at 2.8 A resolution.

The structure of R-phycoerythrin (R-PE) from Polysiphonia urceolata was determined at 2.8 A resolution. The crystals belong to space group R3 with unit cell dimensions of a = b = 189.8 A, c = 60.1 A. The subunit composition of R-PE is (alpha 2 beta 2)3 gamma. The three-dimensional structure of R-PE was solved by the multiple isomorphous replacement method. After several cycles of model building and refinement, the crystallographic R-factor of the final model is 18.0% with data from 10.0 to 2.8 A resolution. The four phycoerythrobilin chromophores alpha 84, alpha 140a, beta 84 and beta 155 in an (alpha beta) unit are each covalently bound to a cysteine residue through ring A. The phycourobilin chromophore is bound to cysteine beta 50 by ring A and bound to cysteine beta 61 by ring D. The ring A and ring D of phycourobilin deviate from the conjugate plane formed by ring B and ring C and the four rings form a boat-shaped structure. R-PE contains a 34 kDa gamma subunit that is assumed to lie in the central channel of the molecular disc (alpha 2 beta 2)3. The energy transfer and relationship between cysteine residues and chromophores are discussed.