Molecular understanding and clinical outcomes of CAR T cell therapy in the treatment of urological tumors.

Chimeric antigen receptor engineered T (CAR T) cell therapy has developed rapidly in recent years, leading to profound developments in oncology, especially for hematologic malignancies. However, given the pressure of immunosuppressive tumor microenvironments, antigen escape, and diverse other factors, its application in solid tumors is less developed. Urinary system tumors are relatively common, accounting for approximately 24% of all new cancers in the United States. CAR T cells have great potential for urinary system tumors. This review summarizes the latest developments of CAR T cell therapy in urinary system tumors, including kidney cancer, bladder cancer, and prostate cancer, and also outlines the various CAR T cell generations and their pathways and targets that have been developed thus far. Finally, the current advantages, problems, and side effects of CAR T cell therapy are discussed in depth, and potential future developments are proposed in view of current shortcomings.

Electric field control of perpendicular magnetic tunnel junctions with easy-cone magnetic anisotropic free layers.

Magnetic tunnel junctions (MTJs) are the core element of spintronic devices. Currently, the mainstream writing operation of MTJs is based on electric current with high energy dissipation, and it can be notably reduced if an electric field is used instead. In this regard, it is promising for electric field control of MTJ in the multiferroic heterostructure composed of MTJ and ferroelectrics via strain-mediated magnetoelectric coupling. However, there are only reports on MTJs with in-plane anisotropy so far. Here, we investigate electric field control of the resistance state of MgO-based perpendicular MTJs with easy-cone anisotropic free layers through strain-mediated magnetoelectric coupling in multiferroic heterostructures. A remarkable, nonvolatile, and reversible modulation of resistance at room temperature is demonstrated. Through local reciprocal space mapping under different electric fields for Pb(Mg1/3Nb2/3)0.7Ti0.3O3 beneath the MTJ pillar, the modulation mechanism is deduced. Our work represents a crucial step toward electric field control of spintronic devices with non-in-plane magnetic anisotropy.

Electric-field control of nonvolatile resistance state of perpendicular magnetic tunnel junction via magnetoelectric coupling.

Magnetic tunnel junctions (MTJs) are the core elements of spintronic devices. Now, the mainstream writing operation of MTJs mainly relies on electric current with high energy dissipation, which can be greatly reduced if an electric field is used instead. In this regard, strain-mediated multiferroic heterostructure composed of MTJ and ferroelectrics are promising with the advantages of room temperature and magnetic field-free as already demonstrated by MTJ with in-plane magnetic anisotropy. However, there is no such report on the perpendicular MTJs (p-MTJs), which have been commercialized. Here, we investigate electric-field control of resistance state of MgO-based p-MTJs in multiferroic heterostructures. A remarkable and nonvolatile manipulation of resistance is demonstrated at room temperature without magnetic field assistance. Through various characterizations and micromagnetic simulation, the manipulation mechanism is uncovered. Our work provides an effective avenue for manipulating p-MTJ resistance by electric fields and is notable for high density and ultralow power spintronic devices.

Identification and validation of a glycolysis-related taxonomy for improving outcomes in glioma.

BACKGROUND: Reprogramming of glucose metabolism is a prominent abnormal energy metabolism in glioma. However, the efficacy of treatments targeting glycolysis varies among patients. The present study aimed to classify distinct glycolysis subtypes (GS) of glioma, which may help to improve the therapy response. METHODS: The expression profiles of glioma were downloaded from public datasets to perform an enhanced clustering analysis to determine the GS. A total of 101 combinations based on 10 machine learning algorithms were performed to screen out the most valuable glycolysis-related glioma signature (GGS). Through RSF and plsRcox algorithms, adrenomedullin (ADM) was eventually obtained as the most significant glycolysis-related gene for prognostic prediction in glioma. Furthermore, drug sensitivity analysis, molecular docking, and in vitro experiments were utilized to verify the efficacy of ADM and ingenol mebutate (IM). RESULTS: Glioma patients were classified into five distinct GS (GS1-GS5), characterized by varying glycolytic metabolism levels, molecular expression, immune cell infiltration, immunogenic modulators, and clinical features. Anti-CTLA4 and anti-PD-L1 antibodies significantly improved the prognosis for GS2 and GS5, respectively. ADM has been identified as a potential biomarker for targeted glycolytic therapy in glioma patients. In vitro experiments demonstrated that IM inhibited glioma cell progression by inhibiting ADM. CONCLUSION: This study elucidates that evaluating GS is essential for comprehending the heterogeneity of glioma, which is pivotal for predicting immune cell infiltration (ICI) characterization, prognosis, and personalized immunotherapy regimens. We also explored the glycolysis-related genes ADM and IM to develop a theoretical framework for anti-tumor strategies targeting glycolysis.

Gut microbiota composition alteration analysis and functional categorization in children with growth hormone deficiency.

Objective: To study changes in the composition and functions of the gut microbiota (GM) in children with growth hormone deficiency (GHD) using high-throughput sequencing. Methods: Thirty-three children with GHD diagnosed in Longgang District Maternity and Child Health Hospital were included in the disease group and 24 healthy children of the same age comprised the control group. Total DNA was extracted and amplified from stool samples obtained from all subjects. High-throughput sequencing was used to analyze the GM composition and functions. Results: The GM from the two groups of children showed significant differences in α-diversity (P < 0.05). In comparison with the control group, the abundance of the phylum Bacteroidetes was significantly higher (45.96% vs. 65.71%) while the Firmicutes count was significantly lower (47.09% vs. 25.20%). At the genus level, the abundance of Prevotella in the disease group was significantly higher (3.16% vs. 20.67%) and that of Lachnospiracea incertae sedis, Clostridium XlVa, and Megamonas was lower (6.576% vs. 1.75%; 4.51% vs. 0.80%; 5.08% vs. 2.02%, respectively). GM functions, including those involved in membrane_transport, energy_metabolism, poorly_characterized, metabolism_of_cofactors_and_vitamins, glycan_biosynthesis_and_metabolism, transcription, folding,_sorting,_and_degradation, were significantly altered in the disease group. The abundance of various GM components was correlated with endocrine hormone levels. Conclusion: Significant alterations in the GM are seen in children with growth hormone deficiency, which may affect both energy metabolism and the levels of endocrine hormones, potentially leading to growth restriction.

Bulbiferamide, an Antitrypanosomal Hexapeptide Cyclized via an N-Acylindole Linkage from a Marine Obligate Microbulbifer.

UV absorption spectroscopy-guided fractionation of the culture extract of a marine obligate bacterium of the genus Microbulbifer yielded a novel cyclic hexapeptide, bulbiferamide (1). NMR spectroscopic and mass spectrometric analyses revealed the structure of 1 to be a cyclic tetrapeptide appending a ureido-bridged two amino acid unit. Notably, Trp is a junction residue, forming on one hand a very rare N-aminoacylated indole linkage for cyclization and on the other hand connecting the ureido-containing tail structure, which is an unprecedented way of configuring peptides. The component amino acids were determined to be l by the advanced Marfey's method. Compound 1 displayed growth inhibitory activity against Trypanosoma cruzi epimastigotes with an IC50 value of 4.1 µM, comparable to the currently approved drug benznidazole, while it was not cytotoxic to P388 murine leukemia cells at 100 µM.

Experimental demonstration of skyrmionic magnetic tunnel junction at room temperature.

Chiral magnetic skyrmions are topological swirling spin textures that hold promise for future information technology. The electrical nucleation and motion of skyrmions have been experimentally demonstrated in the last decade, while electrical detection compatible with semiconductor processes has not been achieved, and this is considered one of the most crucial gaps regarding the use of skyrmions in real applications. Here, we report the direct observation of nanoscale skyrmions in CoFeB/MgO-based magnetic tunnel junction devices at room temperature. High-resolution magnetic force microscopy imaging and tunneling magnetoresistance measurements are used to illustrate the electrical detection of skyrmions, which are stabilized under the cooperation of interfacial Dzyaloshinskii-Moriya interaction, perpendicular magnetic anisotropy, and dipolar stray field. This skyrmionic magnetic tunnel junction shows a stable nonlinear multilevel resistance thanks to its topological nature and tunable density of skyrmions under current pulse excitation. These features provide important perspectives for spintronics to realize high-density memory and neuromorphic computing.

Krasilnikolides A and B and Detalosylkrasilnikolide A, Cytotoxic 20-Membered Macrolides from the Genus Krasilnikovia: Assignment of Anomeric Configuration by J-Based Configuration Analysis.

A chemical investigation of strain RD003821, belonging to the underexplored actinomycetes genus Krasilnikovia, led to the discovery of three novel polyketides: two 20-membered glycomacrolides, krasilnikolides A (1) and B (2), and an aglycone of 1, detalosylkrasilnikolide A (3). A major challenge in the structure elucidation of 1 was to determine the anomeric configuration of the α-l-6-deoxytalose (6dTal) unit, which was achieved by J-based configuration analysis (JBCA) that incorporated anomeric carbon- and proton-specific two-bond 13C-1H spin-spin coupling constants as diagnostic parameters. The updated criteria for the conformation/configuration assignment facilitated discrimination of three out of four stereochemical variants at the anomeric and the adjacent C2 positions, which expanded the scope of the JBCA method to determination of the anomeric configuration of aldohexopyranoses. Compounds 1 and 2 are the first macrolides decorated by 6dTal. Compounds 1-3 exhibited cytotoxicity against P388 murine leukemia cells with IC50 values of 14, 8.4, and 3.9 µM, respectively. In addition, 1-3 were antibacterial against the Gram-positive bacterium Kocuria rhizophila with MIC values of 25, 50, and 100 µg/mL. 1 was inhibitory against Staphylococcus aureus with an MIC of 50 µg/mL.

Reversal of the Pinning Direction in the Synthetic Spin Valve with a NiFeCr Seed Layer.

The effect of the seed layers on the magnetic properties of the giant magnetoresistance thin films has received a lot of attention. Here, a synthetic spin valve film stack with a wedge-shaped NiFeCr seed layer is deposited and annealed following a zero-field cooling procedure. The film crystallinity and magnetic properties are studied as a function of the NiFeCr seed layer thickness. It is found that the exchange coupling field from the IrMn/CoFe interface and the antiferromagnetic coupling field in the synthetic antiferromagnet both increase as the seed layer thickness increases, indicating the perfection of film texture. In this film, the critical thickness of the NiFeCr seed layer for the formation of the ordered IrMn3 texture is about 9.3 nm. Meanwhile, a reversal of the pinning direction in the film is observed at this critical thickness of NiFeCr. This phenomenon can be explained in a free energy model by the competition effect between the exchange coupling and the interlayer coupling during the annealing process.

Association between preoperative serum Cystatin-C levels and postsurgical oncological prognosis in patients with PRCC: A retrospective cohort study.

OBJECTIVE: Cystatin-C (Cys-C) is a predictor of several malignancies. However, whether Cys-C levels predict prognosis in patients with papillary renal cell carcinoma (PRCC) remains uncertain. The aim of this study was to assess the correlation between Cys-C and clinical outcomes in patients with PRCC. METHODS: The medical records of 137 patients with PRCC who underwent surgery at our institution from January 2008 to December 2020 were retrospectively analyzed. Data were divided into two subgroups based on cutoff values and the relationship between the Cys-C group and their clinical outcomes was assessed. RESULTS: By the last follow-up, 62 patients had died of various causes, 53 of whom died from PRCC. Sixty patients suffered recurrence or metastasis during follow-up. Based on the cutoff value, the patients were divided into two groups: low Cys-C group (Cys-C < 1.25 mg/L, n = 92) and high Cys-C group (Cys-C ≥ 1.25 mg/L, n = 45). Pathological classification and serum Cys-C levels were shown to be independent prognostic factors affecting clinical outcomes, according to multivariate Cox regression analysis (p < 0.05). After adjusting the Cox proportional hazards model, the risk of death was elevated in the high Cys-C group. The results of the area under the curve for time-dependent receiver operating characteristics analysis indicated that Cys-C is a stable and reliable prognostic biomarker for predicting survival in patients with PRCC. Forest plots, constructed to better reflect the comparison of hazard ratios between the two groups, confirmed that Cys-C levels were significantly associated with worsening overall survival. CONCLUSION: This study is the first to examine the relationship between preoperative serum Cys-C levels and prognostic overall survival in patients with PRCC. Cys-C may be a useful biomarker for preoperative screening of high-risk patients who may require adjuvant therapy.

Trehangelin E, a bisacyl trehalose with plant growth promoting activity from a rare actinomycete Polymorphospora sp. RD064483.

Trehangelin E (1), a new bisacyl trehalose, was isolated from the culture extract of an actinomycete Polymorphospora sp. RD064483, along with three known congeners, trehangelins A, B, and D. Compound 1 is a new trehalose derivative acylated with (Z)-2-methyl-2-butenoic acid (angelic acid) at 3- and 6'-positions, as determined by NMR and MS analyses. Compound 1 promoted root elongation of germinated lettuce seeds by 30% at 1 µM and 90% at 10 µM compared to the nontreated seeds. Similar promoting activity of root elongation was also observed with trehangelins A and B at the same level.

Association Between the Pretreatment Albumin-to-Alkaline Phosphatase Ratio and Clinical Outcomes in Patients With Bladder Cancer Treated With Radical Cystectomy: A Retrospective Cohort Study.

OBJECTIVE: Serum albumin-to-alkaline phosphatase ratio (AAPR) has been proven to be a prognostic indicator of many malignant tumors. However, whether it can predict the prognosis of bladder cancer (BC) patients who underwent radical cystectomy (RC) remains unclear. This study was designed to assess the relationship between AAPR and clinical outcomes in patients with BC treated with RC. METHODS: The clinicopathological data of 199 BC patients receiving RC in our institution from January 2012 to December 2017 were retrospectively collected and analyzed. They were divided into three groups based on the optimal cut-off values and the association between AAPR groups and their clinical outcomes were evaluated. RESULTS: The average age of the patients was (64.0 ± 8.7) years and 79.9% were male. Based on the cut-off values of AAPR, patients were divided into three groups: low-AAPR group (AAPR < 0.37, n = 35), medium-AAPR group (AAPR = 0.37-0.59, n = 61) and high-AAPR group (AAPR > 0.59, n = 103). The median overall survival (OS) of each AAPR group was 12.5, 24, and 29 months, respectively (P value <0.0001). After adjusting the Cox proportional hazards model, medium- and high- AAPR groups showed a reduced risk trend of death, with a risk ratio of 0.44 (95% CI = 0.21-0.91) and 0.25 (95% CI = 0.12-0.49), respectively (P for trend <0.001). No nonlinear relationship was identified by smooth fitting curve between AAPR and OS. By subgroup analysis, we observed that compared to the low-AAPR group, the trends of the HRs in the medium- and high-AAPR group were decreased across nearly all subgroups after stratification. Moreover, the AAPR-based nomograms for OS, CSS and RFS were also constructed. The C-index showed a good predictive accuracy (OS, C-index 0.728, 95% CI 0.663-0.793; CSS, C-index 0.792, 95% CI 0.748-0.838; RFS, C-index 0.784, 95% CI 0.739-0.829). CONCLUSION: Pretreatment AAPR is significantly associated with the prognosis of BC patients receiving RC, which can be conducive to the clinical decision-making and risk stratification in those patients. The nomogram based on AAPR is a reliable model for predicting survival of BC patients after RC.

Enhanced interfacial Dzyaloshinskii-Moriya interactions in annealed Pt/Co/MgO structures.

The interfacial Dzyaloshinskii-Moriya interaction (iDMI) is attracting great interest for spintronics. An iDMI constant larger than 3 mJ m-2 is expected to minimize the size of skyrmions and to optimize the domain-wall dynamics. In this study, we experimentally demonstrate a giant iDMI in Pt/Co/X/MgO ultra-thin film structures with perpendicular magnetization. The iDMI constants were measured using a field-driven creep regime domain expansion method. The enhancement of iDMI with an atomically thin insertion of Ta and Mg is comprehensively understood with the help of ab-initio calculations. Thermal annealing has been used to crystallize the MgO thin layer to improve the tunneling magneto-resistance (TMR), but interestingly it also provides a further increase of the iDMI constant. An increase of the iDMI constant of up to 3.3 mJ m-2 is shown, which is promising for the scaling down of skyrmion electronics.

Efficient nonparametric belief propagation for pose estimation and manipulation of articulated objects.

Robots working in human environments often encounter a wide range of articulated objects, such as tools, cabinets, and other jointed objects. Such articulated objects can take an infinite number of possible poses, as a point in a potentially high-dimensional continuous space. A robot must perceive this continuous pose to manipulate the object to a desired pose. This problem of perception and manipulation of articulated objects remains a challenge due to its high dimensionality and multimodal uncertainty. Here, we describe a factored approach to estimate the poses of articulated objects using an efficient approach to nonparametric belief propagation. We consider inputs as geometrical models with articulation constraints and observed RGBD (red, green, blue, and depth) sensor data. The described framework produces object-part pose beliefs iteratively. The problem is formulated as a pairwise Markov random field (MRF), where each hidden node (continuous pose variable) is an observed object-part's pose and the edges denote the articulation constraints between the parts. We describe articulated pose estimation by a "pull" message passing algorithm for nonparametric belief propagation (PMPNBP) and evaluate its convergence properties over scenes with articulated objects. Robot experiments are provided to demonstrate the necessity of maintaining beliefs to perform goal-driven manipulation tasks.

Distinguishing Interface Magnetoresistance and Bulk Magnetoresistance through Rectification of Schottky Heterojunctions.

High performance of many spintronic devices strongly depends on the spin-polarized electrical transport, especially the magnetoresistance (MR) in magnetic heterojunctions. However, it has been a great challenge to distinguish the bulk MR and interface MR by transport measurements because the bulk resistance and interface resistance formed a series circuit in magnetic heterojunctions. Here, a unique interface-sensitive rectification MR method is proposed to distinguish the interface MR and bulk MR of nonmagnetic In/GeO x/n-Ge and magnetic Co/GeO x/n-Ge diode-like heterojunctions. It is demonstrated that the low-field "butterfly" hysteresis loop observed only in the conventional MR curve originates from the anisotropic MR of ferromagnetic bulk Co layer, whereas the orbit-related large nonsaturating positive MR contains contributions from both the Schottky interface and bulk Ge substrate. This rectification MR method could be extended to magnetic heterojunctions with asymmetric potential barriers to realize a deeper understanding of the fundamental interface-related functionalities.

Sparse appearance learning based automatic coronary sinus segmentation in CTA.

Interventional cardiologists are often challenged by a high degree of variability in the coronary venous anatomy during coronary sinus cannulation and left ventricular epicardial lead placement for cardiac resynchronization therapy (CRT), making it important to have a precise and fully-automatic segmentation solution for detecting the coronary sinus. A few approaches have been proposed for automatic segmentation of tubular structures utilizing various vesselness measurements. Although working well on contrasted coronary arteries, these methods fail in segmenting the coronary sinus that has almost no contrast in computed tomography angiography (CTA) data, making it difficult to distinguish from surrounding tissues. In this work we propose a multiscale sparse appearance learning based method for estimating vesselness towards automatically extracting the centerlines. Instead of modeling the subtle discrimination at the low-level intensity, we leverage the flexibility of sparse representation to model the inherent spatial coherence of vessel/background appearance and derive a vesselness measurement. After centerline extraction, the coronary sinus lumen is segmented using a learning based boundary detector and Markov random field (MRF) based optimal surface extraction. Quantitative evaluation on a large cardiac CTA dataset (consisting of 204 3D volumes) demonstrates the superior accuracy of the proposed method in both centerline extraction and lumen segmentation, compared to the state-of-the-art.

[Characteristics of spatial variation of soil nutrients in sloping field in a gorge karst region, southwest China].

Based on a grid (20 m x 20 m) sampling, spatial heterogeneity and pattern of soil nutrients in sloping field in the gorge karst region, southwestern China, were explored by using classical statistics and geostatistics methods. The results showed that soil nutrient contents in slope field in the canyon karst region were more abundant, where pH value had a weak variation and the soil organic matter (SOM) had a moderate degree of variation. All the soil nutrients had moderate or strong variation with an order of available phosphorus (AP) > total potassium (TK) > SOM > alkaline nitrogen (AN) > total nitrogen (TN) > total phosphorus (TP) > available potassium (AK). All of the soil nutrients had a good spatial autocorrelation and the autocorrelation function performed in the same law of developing from positive to negative direction with the inflection point ranged from 80 to 100 m. In addition, the Moran's I was small for TK and AP while large for other nutrients. Characteristics of spatial variation differed among soil nutrients. Exponential model fitted best for TK and AP, in which the ratio of nugget to sill (C0/(C0 + C)) and the range (A) were small and the fractal dimension (D) was high, showed a strong spatial correlation. Spherical model fitted best for other soil nutrients, with C0/(C0 + C) , the range (A) and D showing a moderate autocorrelation. Kriging analysis clearly indicated that pH, SOM, TN, TP and AN were distributed in a concave pattern, while AP and AK had fragmented patch distribution. Therefore, vegetation, topography, human disturbance and strong heterogeneity of microhabitats are main factors leading to the differences in patterns of soil nutrients on the sloping land in the gorge karst region.

[Compositional characteristics and roles of soil mineral substances in depressions between hills in karst region].

Based on the investigation and analysis of seven soil mineral substance variables, nine vegetation factors, four topographical factors, and ten soil physicochemical factors in the 200 m x 40 m dynamic monitoring plots in farmland, forest plantation, secondary forest, and primary forest in the depressions between hills in karst region, and by using traditional statistical analysis, principal component analysis (PCA), and canonical correlation analysis (CCA), this paper studied the compositional characteristics and roles of soil mineral substances as well as the coupling relationships between the mineral substances and the vegetation, topography, and other soil properties. In the depressions, soil mineral substances were mainly composed of SiO2, Al2O3, K2O, and Fe2O3, whose contents were obviously lower than the mean background values of the soils in the world and in the zonal red soils at the same latitudes. The soil CaO and MgO contents were at medium level, while the soil MnO content was very low. The composition of soil mineral substances and their variation degrees varied with the ecosystems, and the soil development degree also varied. There was a positive correlation between vegetation origin and soil origin, suggesting the potential risk of rock desertification. Due to the high landscape heterogeneity of the four ecosystems, PCA didn't show good effect in lowering dimension. In all of the four ecosystems, soil mineral substances were the main affecting factors, and had very close relationships with vegetation, topography, and other soil properties. Especially for SiO2, CaO, and MnO, they mainly affected the vegetation species diversity and the soil organic matter, total nitrogen, and total potassium. This study indicated that soil mineral substances were the one of the factors limiting the soil fertility and vegetation growth in the depressions between hills in karst region. To effectively use the soil mineral resources and rationally apply mineral nutrients would have significances in the restoration and reconstruction of karst degraded ecosystems.

Direct laser interference ablating nanostructures on organic crystals.

Two-beam interference ablation of 1,4-Bis(4-methylstyryl)benzene organic crystal by short laser pulses (10 ns, 355 nm) is presented. The influence of laser fluence, interference period, and pulse number on the morphology have been studied. The morphology is closely associated with the molecular interactions in the crystals, and it could be well controlled by adjusting the laser fluence and pulses number. Through interference ablating the crystals with high fluence pulses, and then treated with low fluence laser pulses, grating structures with smooth surface could be fabricated without any additional process.