Miracle-dz/UniFAR-FTUs huggingface dataset:
The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice

Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.
An Insertion Mutation in Bra032169 Encoding a Histone Methyltransferase Is Responsible for Early Bolting in Chinese Cabbage (Brassica rapa L. ssp. pekinensis)

Bolting is an important agronomic character of the Chinese cabbage, but premature bolting can greatly reduce its commercial value, yield, and quality. Here, early-bolting mutant 1 (ebm1) was obtained from a Chinese cabbage doubled haploid (DH) line “FT,” by using an isolated microspore culture and ethyl methanesulfonate (EMS) mutagenesis. The ebm1 was found to bolt extremely earlier than the wild type “FT. ” Genetic analysis indicated that the phenotype of the ebm1 was controlled by a single recessive nuclear gene. Using a mapping population of 1,502 recessive homozygous F2 individuals with the ebm1 phenotype, the ebm1 gene was mapped to between the markers SSRhl-53 and SSRhl-61 on chromosome A04 by using SSR markers, and its physical distance was 73.4 kb. Seven genes were predicted in the target region and then cloned and sequenced; the only difference in the sequences of the ebm1 and “FT” genes was with Bra032169. Unlike that in “FT,” the Bra032169 in ebm1 had a novel 53 bp insertion that caused the termination of amino acid coding. The mutation was not consistent with EMS mutagenesis, and thus, may have been caused by spontaneous mutations during the microspore culture. Based on the gene annotation information, Bra032169 was found to encode the histone methyltransferase CURLY LEAF (CLF) in Arabidopsis thaliana. CLF regulates the expression of flowering-related genes. Further genotyping revealed that the early-bolting phenotype was fully co-segregated with the insertion mutation, suggesting that Bra032169 was the most likely candidate gene for ebm1. No significant differences were noted in the Bra032169 expression levels between the ebm1 and “FT. ” However, the expression levels of the flowering-related genes FLC, FT, AG, and SEP3 were significantly higher in the ebm1 than in the “FT. ” Thus, the mutation of Bra032169 is responsible for the early-bolting trait in Chinese cabbage. These results provide foundation information to help understand the molecular mechanisms of bolting in the Chinese cabbage.
Cytogenetic studies in Camellia. I

1. Following varieties of Camellia were used for the present chromosome survey: each one variety of Camellia assimilis, C. granthamiana and of C. hiemalis, 14 varieties of C. japonica, 3 varieties of C. japonica subsp. rusticana, each one of C. salicifolia and of C. saluenensis and 3 of C. spp. (not identified). The karyotype analysis was also carried out with several representative forms.2. Following different karyotypes were clearly discriminated:C. japonica K(2n)=16V+8J+2Jt+4vC. japonic subsp. rusticana (a wild variety) K(2n)=16V+8J+J1t+J2t+4vC. salicifolia K(2n)=16V+8J+2Jt+4vC. saluenensis var. Seiobo K(2n)=17V+7J+J1t+J2t+4vA wild form of C. japonica subsp. rusticana and a cultivated form, “Seiobo”, of C. saluenensis were considered presumably to be either structural chromosome hybrids or true hybrid forms.3. Result of the present chromosome survey was compiled in Table 1 and whole the data hitherto reported by many workers were represented on the list in appendix. The present authors could reveal following new facts: (i) C. assimilis was considered to be a diploid species. (ii) A hypo-triploid (3x-1) and a pentaploid forms were first discovered in C. japonica. (iii)“Otani-totsubaki”, a variety of C. reticulate, was composed of 91 somatic chromosomes including a small supernumerary chromosome. (iv) Horticultural varieties, “Tamuke-yama”and“Umegaka”, were of tetraploid chromosome constitution.4. The polyploid series in Camellia ranged between 2x(2n=30) and 8x(2n=120) forms. More than half of species studied were the polyploid species or the species showing intraspecific differentiation of polyploidy. There could be noticed remarkable prevalence of 3x and 6x forms in clearcut contrast to the rather slight occurrence of 4x forms, and such situation would strongly suggest that the triploidy had an important role for the evolution of polyploid series in Camellia.The discovery of 5x and 4x forms in Japonica-camellias, the latter forms being duly considered to be of hybrid origin, will give a great hope for the practical breeding on polyploid level of valuable new forms.
Changes in Intestinal Flora and Metabolites in Neonates With Breast Milk Jaundice

Background: Breast milk jaundice (BMJ) is the first cause of neonatal jaundice; however, its underlying mechanism is yet to be deciphered. We conducted a study to investigate intestinal flora in neonates with BMJ and used metabolomics to decipher the possible mechanisms by which intestinal flora induces jaundice. Methods: Microbiota collected from the feces of BMJ patients and jaundice-free breastfeeding newborns was used for 16S rRNA sequencing. In addition, differences in fecal metabolites were analyzed using gas chromatography mass spectrometry (GC/MS). The relationship between intestinal microbiota and the differences in fecal metabolites was then analyzed. Results: There was no significant difference in the richness and diversity of intestinal flora between BMJ and the control group; however, there were differences in the structure. At the phylum level, the relative abundance of Firmicutes was higher in the control group compared to the BMJ group, whereas Proteobacteria was higher in the infants with BMJ. Additionally, at the genus level, the relative abundance of Haemophilus was higher in the control group, whereas the relative abundances of Escherichia, Morganella, and Rothia were lower. More remarkably, the major differences in metabolites between the two groups were glyceric acid, succinic acid, and phenylalanine. Additionally, the abundance of Escherichia was positively correlated with succinic acid and cadaverine levels. Conclusions: The intestinal flora colonization status in BMJ patients is immature. This study reports for the first time that the study of intestinal flora, especially Escherichia, plays an important role in BMJ, and found that it may be associated with the regulation of succinic acid metabolic pathways.
Characterizing Retinal Ganglion Cell Responses to Electrical Stimulation Using Generalized Linear Models

The ability to preferentially stimulate different retinal pathways is an important area of research for improving visual prosthetics. Recent work has shown that different classes of retinal ganglion cells (RGCs) have distinct linear electrical input filters for low-amplitude white noise stimulation. The aim of this study is to provide a statistical framework for characterizing how RGCs respond to white-noise electrical stimulation. We used a nested family of Generalized Linear Models (GLMs) to partition neural responses into different components—progressively adding covariates to the GLM which captured non-stationarity in neural activity, a linear dependence on the stimulus, and any remaining non-linear interactions. We found that each of these components resulted in increased model performance, but that even the non-linear model left a substantial fraction of neural variability unexplained. The broad goal of this paper is to provide a much-needed theoretical framework to objectively quantify stimulus paradigms in terms of the types of neural responses that they elicit (linear vs. non-linear vs. stimulus-independent variability). In turn, this aids the prosthetic community in the search for optimal stimulus parameters that avoid indiscriminate retinal activation and adaptation caused by excessively large stimulus pulses, and avoid low fidelity responses (low signal-to-noise ratio) caused by excessively weak stimulus pulses.
Predicting Progression-Free Survival Using MRI-Based Radiomics for Patients With Nonmetastatic Nasopharyngeal Carcinoma

Objectives: This study aimed to explore the predictive value of MRI-based radiomic model for progression-free survival (PFS) in nonmetastatic nasopharyngeal carcinoma (NPC). Methods: A total of 327 nonmetastatic NPC patients [training cohort (n = 230) and validation cohort (n = 97)] were enrolled. The clinical and MRI data were collected. The least absolute shrinkage selection operator (LASSO) and recursive feature elimination (RFE) were used to select radiomic features. Five models [Model 1: clinical data, Model 2: overall stage, Model 3: radiomics, Model 4: radiomics + overall stage, Model 5: radiomics + overall stage + Epstein–Barr virus (EBV) DNA] were constructed. The prognostic performances of these models were evaluated by Harrell's concordance index (C-index). The Kaplan–Meier method was applied for the survival analysis. Results: Model 5 incorporating radiomics, overall stage, and EBV DNA yielded the highest C-indices for predicting PFS in comparison with Model 1, Model 2, Model 3, and Model 4 (training cohorts: 0.805 vs. 0.766 vs. 0.749 vs. 0.641 vs. 0.563, validation cohorts: 0.874 vs. 0.839 vs. 836 vs. 0.689 vs. 0.456). The survival curve showed that the high-risk group yielded a lower PFS than the low-risk group. Conclusions: The model incorporating radiomics, overall stage, and EBV DNA showed better performance for predicting PFS in nonmetastatic NPC patients.
The Association Between Prolactin and Metabolic Parameters in PCOS Women: A Retrospective Analysis

Background: The aim of this retrospective study was to analyze the association between prolactin (PRL) and metabolic parameters in infertile patients with polycystic ovary syndrome (PCOS). Methods: A total of 2,052 patients with PCOS and 9,696 patients with tubal infertility (non-PCOS) undergoing in vitro fertilization and embryo transfer (IVF-ET) at the reproductive medicine center of the first affiliated hospital of Wenzhou Medical University from January 2007 to July 2017 were enrolled in this study. Serum PRL, basic endocrine hormones, fasting plasma lipid, fasting plasma glucose (FPG), liver function, thyroid hormone and other parameters were measured and analyzed. Result: PRL levels were significantly lower in PCOS patients than controls over all age groups (p < 0.05). In the PCOS patients, serum PRL was significantly and positively correlated with FPG, serum TSH and serum FT4, and significantly and negatively correlated with LH, LH/FSH, TC, TG, LDL-C, AST, ALT, γ-GGT, FT3, and FT3/FT4 (p < 0.05 or 0.01). After adjusted for age and body mass index (BMI), serum PRL was positively correlated with FPG, TSH, and FT4, and negatively correlated with LH and LH/FSH. Conclusion: Low serum PRL may be an important cause of metabolic risk in infertile patients with PCOS.
Effect of inorganic phosphatic fertilizers on the efficacy of an arbuscular mycorrhiza fungus against a root-knot nematode on pyrethrum

Effects of triple super phosphate (TSP) and single super phosphate (SSP) fertilizers on efficacy of a Glomus sp. (isolate KS 14) against Meloidogyne hapla were determined. The fertilizers were applied at 150 and 300 kg ha -1 at the time of fungus inoculation. Two months later, plants were inoculated with the nematodes. Plant growth and nematode disease parameters were determined 2 months after nematode inoculation. The fertilizers at both levels improved plant growth in all treatments. In general, the fungus improved plant growth on its own or in the presence of nematodes, but not in the presence of fertilizers. Both fertilizers at both levels were more effective in improving plant growth than the fungus. The fungus showed sensitivity to inorganic P fertilizers in that the fertilizers significantly reduced fungal root colonization and its pyrethrum growth stimulative effects. The fungus suppressed nematode disease severity unlike the fertilizers. The suppressive effects of the fungus on the nematodes were in most cases reduced by the fertilizers. The nematodes, unlike the fertilizers, did not have any significant effects on root colonization by the fungus or on its ability to improve pyrethrum growth. The presence of nematodes in fertilizer or fertilizer-fungus-treated plants, however, significantly reduced pyrethrum growth.
Genetic Diversity and Evolutionary Analyses Reveal the Powdery Mildew Resistance Gene Pm21 Undergoing Diversifying Selection

Wheat powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt) is a devastating disease that threatens wheat production and yield worldwide. The powdery mildew resistance gene Pm21, originating from wheat wild relative Dasypyrum villosum, encodes a coiled-coil, nucleotide-binding site, leucine-rich repeat (CC-NBS-LRR) protein and confers broad-spectrum resistance to wheat powdery mildew. In the present study, we isolated 73 Pm21 alleles from different powdery mildew-resistant D. villosum accessions, among which, 38 alleles were non-redundant. Sequence analysis identified seven minor insertion-deletion (InDel) polymorphisms and 400 single nucleotide polymorphisms (SNPs) among the 38 non-redundant Pm21 alleles. The nucleotide diversity of the LRR domain was significantly higher than those of the CC and NB-ARC domains. Further evolutionary analysis indicated that the solvent-exposed LRR residues of Pm21 alleles had undergone diversifying selection (dN/dS = 3.19734). In addition, eight LRR motifs and four amino acid sites in the LRR domain were also experienced positive selection, indicating that these motifs and sites play critical roles in resistance specificity. The phylogenetic tree showed that 38 Pm21 alleles were divided into seven classes. Classes A (including original Pm21), B and C were the major classes, including 26 alleles (68.4%). We also identified three non-functional Pm21 alleles from four susceptible homozygous D. villosum lines (DvSus-1 to DvSus-4) and two susceptible wheat-D. villosum chromosome addition lines (DA6V#1 and DA6V#3). The genetic variations of non-functional Pm21 alleles involved point mutation, deletion and insertion, respectively. The results also showed that the non-functional Pm21 alleles in the two chromosome addition lines both came from the susceptible donors of D. villosum. This study gives a new insight into the evolutionary characteristics of Pm21 alleles and discusses how to sustainably utilize Pm21 in wheat production. This study also reveals the sequence variants and origins of non-functional Pm21 alleles in D. villosum populations.
Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be synthesized de novo starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to re-form NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.
Low-Dose Crizotinib, a Tyrosine Kinase Inhibitor, Highly and Specifically Sensitizes P-Glycoprotein-Overexpressing Chemoresistant Cancer Cells Through Induction of Late Apoptosis in vivo and in vitro

We investigated possible conditions or drugs that could target P-glycoprotein (P-gp)-overexpressing drug-resistant KBV20C cancer cells. Specifically, we focused on identifying a single treatment with a relatively low half maximal inhibitory concentration (IC50). Our approach utilized repurposing drugs, which are already used in clinical practice. We evaluated 13 TKIs (gefitinib, imatinib, erlotinib, nilotinib, pazopanib, masatinib, sunitinib, sorafenib, regorafenib, lapatinib, vandetanib, cediranib, and crizotinib) for their sensitizing effects on P-gp-overexpressing drug-resistant KBV20C cells. We found that crizotinib had a much greater sensitization effect than the other tested drugs at relatively low doses. In a detailed quantitative analysis using both lower doses and time-duration treatments, we demonstrated that crizotinib, which increased the levels of apoptosis and G2 arrest, was the best TKI to induce sensitization in P-gp-overexpressing KBV20C cells. Upon comparing resistant KBV20C cells and sensitive KB parent cells, crizotinib was found to markedly sensitize drug-resistant KBV20C cancer cells compared with other TKIs. This suggests that crizotinib is a resistant cancer cell-sensitizing drug that induces apoptosis. In mice bearing xenografted P-gp-overexpressing KBV20C cells, we confirmed that crizotinib significantly reduced tumor growth and weight, without apparent side effects. In addition, although lapatinib and crizotinib have a high P-gp inhibitory activity, we found that co-treatment with crizotinib and vincristine (VIC) did not have much of a sensitization effect on KBV20C cells, whereas lapatinib had a high sensitization effect on VIC-treated KBV20C cells. This suggests that crizotinib is a single-treatment specific drug for resistant cancer cells. These findings provide valuable information regarding the sensitization of drug-resistant cells and indicate that low-dose crizotinib monotherapy may be used in patients with specific P-gp-overexpressing chemoresistant cancer.
Nutrient and antinutrient in contents of raw and cooked Amaranthus hybridus

Amaranthus hybridus was grown as a leafy vegetables in four sites in Dar‐Es‐Salaam, Tanzania. Freshly harvested leaves from each of the growing sites were analyzed for proximate composition of beta‐carotene, reduced ascorbic acid, minerals iron, calcium, phosphorous and the antinutrients oxalates and nitrates. The leaves from the four sites were bulked and cooked by boiling in distilled water in the ratio vegetable to water of 1:4 then drained. The drained vegetables were analyzed for beta‐carotene, reduced ascorbic acid, iron, calcium, phosphorus, oxalate and nitrate. Results indicated that fresh amaranth vegetables from the four sites had comparable high moisture contents ranging between 85.3% to 86.5%, protein of between 28.2% to 31.6%. The level of minerals calcium, iron and phosphorus ranged between 2062 mg/100 g and 2263 mg/100 g, 108 mg/100 g and 128 mg/100 g and 500 mg/100 g and 553 mg/100 g respectively on dry weight basis. The levels of beta‐carotene of between 25.2 mg/100 g to 37.3 mg/100 g, ascorbic acid of between 455 mg/100 g to 535 mg/100 g. Nitrates and oxalates were at levels of between 501 mg/100 g to 560 mg/100 g and 3383 mg/100 g to 4333 mg/100 g respectively on dry matter basis. On cooking, the levels of beta‐carotene did not change significantly but there were significant reductions (P < 0.05) in the levels of ascorbic acid of up to 50.4%, and 41.4% for phosphorus, while the total nitrate was reduced by 39.2%, and the oxalate by 40.2%. The study established that Amaranthus hybridus leaves grown in four sites of Dar‐Es‐Salaam were good sources of nutrients, had low nitrates levels but high oxalate contents. Furthermore the cooking losses of the nutrients were not excessive, while the antinutrients were substantially reduced.
Current and Emerging Magnetic Resonance-Based Techniques for Breast Cancer

Breast cancer is the most commonly diagnosed cancer among women worldwide, and early detection remains a principal factor for improved patient outcomes and reduced mortality. Clinically, magnetic resonance imaging (MRI) techniques are routinely used in determining benign and malignant tumor phenotypes and for monitoring treatment outcomes. Static MRI techniques enable superior structural contrast between adipose and fibroglandular tissues, while dynamic MRI techniques can elucidate functional characteristics of malignant tumors. The preferred clinical procedure—dynamic contrast-enhanced MRI—illuminates the hypervascularity of breast tumors through a gadolinium-based contrast agent; however, accumulation of the potentially toxic contrast agent remains a major limitation of the technique, propelling MRI research toward finding an alternative, noninvasive method. Three such techniques are magnetic resonance spectroscopy, chemical exchange saturation transfer, and non-contrast diffusion weighted imaging. These methods shed light on underlying chemical composition, provide snapshots of tissue metabolism, and more pronouncedly characterize microstructural heterogeneity. This review article outlines the present state of clinical MRI for breast cancer and examines several research techniques that demonstrate capacity for clinical translation. Ultimately, multi-parametric MRI—incorporating one or more of these emerging methods—presently holds the best potential to afford improved specificity and deliver excellent accuracy to clinics for the prediction, detection, and monitoring of breast cancer.