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Thirty-two varieties of common and durum wheat, hordeum, barley, and tritordeum collected over two harvesting years (2020 and 2021) were investigated for the presence of multiple Fusarium-related mycotoxins in asymptomatic plants. DON, 3-AcDON, 15-AcDON, T-2, HT-2, and ZEN together with the emerging mycotoxin ENN B and the major modified form of DON, namely DON3Glc, were quantified by means of UHPLC-MS/MS. Overall, DON and ENN B were the most frequently detected mycotoxins, albeit large inter-year variability was observed and related to different climate and weather conditions. Straws had higher mycotoxin contents than kernels and regarding DON occurrence tritordeum was found to be the most contaminated group on average for both harvesting years, while barley was the less contaminated one. Emerging mycotoxin ENN B showed comparable contents in kernels compared to straw, with a ratio close to 1 for tritordeum and barley. Regarding the occurrence of the other evaluated mycotoxins, T-2 and HT-2 toxins have been spotted in a few tritordeum samples, while ZEN has been frequently found only in straw from the harvesting year 2020. The data collected confirms the occurrence of multiple Fusarium mycotoxins in straws also from asymptomatic plants, highlighting concerns related to feed safety and animal health. The susceptibility of Tritordeum, hereby reported for the first time, suggests that careful measures in terms of monitoring, breeding, and cultural choices should be applied when dealing with his emerging crop., (© 2024. The Author(s).)

Spondylolisthesis is defined as the displacement or misalignment of the vertebral bodies one on top of the other. It comes from the Greek spondlylos, which means vertebra, and olisthesis, which means sliding on a slope. The nomenclature used to refer to spondylolisthesis consists of the following elements: vertebral segment (vertebrae involved), degree of sliding of one vertebral body over the other, the position of the upper vertebral body with respect to the lower one (anterolisthesis/retrolisthesis), and finally the etiology [1]., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Maize cropping systems need to be re-designed, within a sustainable intensification context, by focusing on the application of high-use efficiency crop practices, such as those that are able to enhance an early plant vigor in the first critical growth stages; such practices could lead to significant agronomic and yield benefits. The aim of this study has been to evaluate the effects of the cultivation of hybrids with superior early vigor, of the distribution of starter fertilizers at sowing, and of the seed application of biostimulants on promoting plant growth and grain yield in full factorial experiments carried out in both a growth chamber and in open fields. The greatest benefits, in terms of plant growth enhancement (plant height, biomass, leaf area) and cold stress mitigation, were detected for the starter fertilization, followed by the use of an early vigor hybrid and a biostimulant seed treatment. The starter fertilization and the early vigor hybrid led to earlier flowering dates, that is, of 2.1 and 2.8 days, respectively, and significantly reduced grain moisture at harvest. Moreover, the early vigor hybrid, the starter NP fertilization, and the biostimulant treatment increased grain yield by 8.5%, 6.0%, and 5.1%, respectively, compared to the standard hybrid and the untreated controls. The combination of all the considered factors resulted in the maximum benefits, compared to the control cropping system, with an increase in the plant growth of 124%, a reduction of the sowing-flowering period of 5 days, and a gain in grain yield of 14%. When choosing the most suitable crop practice, the diversity of each cropping system should be considered, according to the pedo-climatic conditions, the agronomic background, the yield potential, and the supply chain requirements., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Capo, Sopegno, Reyneri, Ujvári, Agnolucci and Blandino.)

The sustainable intensification of maize-based systems may reduce greenhouse-gas emissions and the excessive use of non-renewable inputs. Considering the key role that the microbiological fertility has on crop growth and resilience, it is worth of interest studying the role of cropping system on the rhizosphere bacterial communities, that affect soil health and biological soil fertility. In this work we monitored and characterized the diversity and composition of native rhizosphere bacterial communities during the early growth phases of two maize genotypes of different early vigor, using a nitrogen (N)-phosphorus (P) starter fertilization and a biostimulant seed treatment, in a growth chamber experiment, by polymerase chain reaction-denaturing gradient gel electrophoresis of partial 16S rRNA gene and amplicon sequencing. Cluster analyses showed that the biostimulant treatment affected the rhizosphere bacterial microbiota of the ordinary hybrid more than that of the early vigor, both at plant emergence and at the 5-leaf stage. Moreover, the diversity indices calculated from the community profiles, revealed significant effects of NP fertilization on richness and the estimated effective number of species ( H 2 ) in both maize genotypes, while the biostimulant had a positive effect on plant growth promoting community of the ordinary hybrid, both at the plant emergence and at the fifth leaf stage. Our data showed that maize genotype was the major factor shaping rhizosphere bacterial community composition suggesting that the root system of the two maize hybrids recruited a different microbiota. Moreover, for the first time, we identified at the species and genus level the predominant native bacteria associated with two maize hybrids differing for vigor. These results pave the way for further studies to be performed on the effects of cropping system and specific crop practices, considering also the application of biostimulants, on beneficial rhizosphere microorganisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ujvári, Capo, Grassi, Cristani, Pagliarani, Turrini, Blandino, Giovannetti and Agnolucci.)

Boron neutron capture therapy (BNCT) is a re-emerging binary cellular level cancer intervention that occurs through the interaction of a cancer-specific 10 boron ( 10 B) drug and neutrons. We created a new 10 B drug, 3-borono-l-tyrosine (BTS), that improves on the characteristics of the main historical BNCT drug 4-borono-l-phenylalanine (BPA). BTS has up to 4 times greater uptake in vitro than BPA and increased cellular retention. Like BPA, BTS uptake is mediated by the l-type amino acid transporter-1 (LAT1) but is less sensitive to natural amino acid competition. BTS can be formulated and bolus dosed at much higher levels than BPA, resulting in 2-3 times greater boron delivery in vivo. Fast blood clearance and greater tumor boron delivery result in superior tumor-to-blood ratios. BTS boron delivery appears to correlate with LAT1 expression. BTS is a promising boron delivery drug that has the potential to improve modern BNCT interventions.

Rye is a secondary crop that is characterized by a higher tolerance to climatically less favorable conditions than other cereal species. For this reason, rye was historically used as a fundamental raw material for bread production and as a supply of straw in northern parts of Europe as well as in mountain environments, such as Alpine valleys, where locally adapted landraces have continued to be cultivated over the years. In this study, rye landraces collected in different valleys in the Northwest Italian Alps have been selected as the most genetically isolated within their geographical contexts and cultivated in two different marginal Alpine environments. The traits concerning their agronomy, mycotoxin contamination, bioactive content, as well as their technological and baking quality were assessed to characterize and compare rye landraces with commercial wheat and rye cultivars. Rye cultivars showed the same grain yield level as wheat in both environments. Only the genotype selected from the Maira Valley was characterized by tall and thin culms and a proneness to lodging, thereby resulting in a lower yield capacity. Among the rye cultivars, the hybrid one presented the highest yield potential, but also the highest susceptibility to the occurrence of ergot sclerotia. However, the rye cultivars, especially the landraces, were characterized by higher concentrations of minerals, soluble fibers, and soluble phenolic acids, and thus both their flours and breads had superior antioxidant properties. A 40% substitution of refined wheat flour with whole-grain rye flour led to a higher dough water absorption and a lower stability, thereby resulting in lower loaf volumes and darker products. Agronomically and qualitatively speaking, the rye landraces diverged significantly from the conventional rye cultivars, thus reflecting their genetic distinctiveness. The landrace from the Maira Valley shared a high content in phenolic acids and good antioxidant properties with the one from the Susa Valley and, when combined with wheat flour, turned out to be the most suitable for bread making. Overall, the results have highlighted the suitability of reintroducing historic rye supply chains, based on the cultivation of local landraces in marginal environments and the production of value-added bakery goods., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sardella, Capo, Adamo, Donna, Ravetto Enri, Vanara, Lonati, Mucciarelli and Blandino.)

Rye ( Secale cereale L.) has been at the basis of agriculture for centuries in most mountainous and northern areas of Eurasia, because it is more resistant than other cereals to low temperatures and poor soils. Rye deserves to be re-evaluated as a source of "environmentally resilient" genes in the future as well, and particularly in a perspective to grow cereals able to withstand global warming. According to recent studies, modern rye varieties have a relatively narrow genetic pool, a condition that is worsening in the most recent breeding processes. The preservation of local landraces as unique sources of genetic diversity has therefore become important, in order to preserve the genetic heritage of rye. In this study, genetic diversity of rye landraces collected in a sector of the Italian Alps particularly suited to traditional agriculture was investigated using the ddRADseq technique. A few landraces still managed with family farming turned out to be genetically distant from the commercial varieties currently in use, highlighting that the phenomenon of homogenization of the local genetic pool can be still circumvented. Ex situ conservation of genetically divergent landraces is a valid tool to avoid the dissipation of an as yet unexplored genetic potential.

AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADCs have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCECs internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts and human umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of poly-glutamate peptides, mutation of residue K16 to D on AGS-16C3F [AGS-16C3F(K16D)], or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCECs and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar antitumor activity in a mouse xenograft model. These findings establish a mechanism of action for target-independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities. Significance: These findings reveal a mechanism for nonreceptor-mediated toxicities of antibody drug conjugates and potential solutions to alleviate these toxicities. Cancer Res; 78(8); 2115-26. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Here, we report the development of an antibody-drug conjugate, ASG-5ME, which targets the solute carrier receptor SLC44A4. SLC44A4 is a member of a family of putative choline transporters that we show to be markedly upregulated in a variety of epithelial tumors, most notably prostate and pancreatic cancer. SLC44A4 is normally expressed on the apical surface of secretory epithelial cells, but in cancer we show expression is not restricted to the luminal surface in advanced and undifferentiated tumors. ASG-5ME consists of a human IgG2 anti-SLC44A4 antibody conjugated through a cleavable linker to the microtubule-disrupting agent monomethylauristatin E. It has potent antitumor activity in both cell line - and patient-derived xenograft models of pancreatic and prostate cancers. Combination studies with ASG-5ME and nab-paclitaxel demonstrated combination effect in both pancreatic and prostate tumor models. Altogether, the data presented here suggest that ASG-5ME may have the potential to offer a new therapeutic option for the treatment of pancreatic and prostate cancers. Mol Cancer Ther; 15(11); 2679-87. ©2016 AACR., (©2016 American Association for Cancer Research.)

SLITRK6 is a member of the SLITRK family of neuronal transmembrane proteins that was discovered as a bladder tumor antigen using suppressive subtractive hybridization. Extensive immunohistochemistry showed SLITRK6 to be expressed in multiple epithelial tumors, including bladder, lung, and breast cancer as well as in glioblastoma. To explore the possibility of using SLITRK6 as a target for an antibody-drug conjugate (ADC), we generated a panel of fully human mAbs specific for SLITRK6. ADCs showed potent in vitro and in vivo cytotoxic activity after conjugation to Monomethyl Auristatin E or Monomethyl Auristatin F. The most potent ADC, ASG-15ME, was selected as the development candidate and given the product name AGS15E. ASG-15ME is currently in phase I clinical trials for the treatment of metastatic urothelial cancer. This is the first report that SLITRK6 is a novel antigen in bladder cancer and also the first report of the development of ASG-15ME for the treatment of metastatic bladder cancer. Mol Cancer Ther; 15(6); 1301-10. ©2016 AACR., (©2016 American Association for Cancer Research.)

The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtractive hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2,394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4. Moderate to strong staining was especially observed in 60% of bladder and 53% of breast tumor specimens, whereas the expression of nectin-4 in normal tissue was more limited. We generated a novel antibody-drug conjugate (ADC) enfortumab vedotin comprising the human anti-nectin-4 antibody conjugated to the highly potent microtubule-disrupting agent MMAE. Hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME) ADC were able to bind to cell surface-expressed nectin-4 with high affinity and induced cell death in vitro in a dose-dependent manner. Treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers with enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4-targeting ADCs. Cancer Res; 76(10); 3003-13. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: New cancer-specific antigens are required for the design of novel antibody-drug conjugates (ADC) that deliver tumor-specific and highly potent cytotoxic therapy., Experimental Design: Suppression subtractive hybridization identified ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) as a potential human cancer-specific antigen. Antibodies targeting the extracellular domain of human ENPP3 were produced and selected for specific binding to ENPP3. Expression of ENPP3 in normal and cancer tissue specimens was evaluated by immunohistochemistry (IHC). ADCs comprising anti-ENPP3 Ab conjugated with maleimidocaproyl monomethyl auristatin F via a noncleavable linker (mcMMAF) were selected for therapeutic potential using binding and internalization assays, cytotoxicity assays, and tumor growth inhibition in mouse xenograft models. Pharmacodynamic markers were evaluated by IHC in tissues and ELISA in blood., Results: ENPP3 was highly expressed in clear cell renal cell carcinoma: 92.3% of samples were positive and 83.9% showed high expression. By contrast, expression was negligible in normal tissues examined, with the exception of the kidney. High expression was less frequent in papillary renal cell carcinoma and hepatocellular carcinoma samples. AGS16F, an anti-ENPP3 antibody-mcMMAF conjugate, inhibited tumor growth in three different renal cell carcinoma (RCC) xenograft models. AGS16F localized to tumors, formed the active metabolite Cys-mcMMAF, induced cell-cycle arrest and apoptosis, and increased blood levels of caspase-cleaved cytokeratin-18, a marker of epithelial cell death., Conclusions: AGS16F is a promising new therapeutic option for patients with RCC and is currently being evaluated in a phase I clinical trial., (©2015 American Association for Cancer Research.)

Preclinical evaluation of novel cancer agents requires models that accurately reflect the biology and molecular characteristics of human tumors. Molecular profiles of eight pancreatic ductal adenocarcinoma patient tumors were compared to corresponding passages of xenografts obtained by grafting tumor fragments into immunocompromised mice. Molecular characterization was performed by copy number analysis, gene expression and microRNA microarrays, mutation analysis, short tandem repeat (STR) profiling, and immunohistochemistry. Xenografts were found to be highly representative of their respective tumors, with a high degree of genetic stability observed by STR profiling and mutation analysis. Copy number variation (CNV) profiles of early and late xenograft passages were similar, with recurrent losses on chromosomes 1p, 3p, 4q, 6, 8p, 9, 10, 11q, 12p, 15q, 17, 18, 20p, and 21 and gains on 1q, 5p, 8q, 11q, 12q, 13q, 19q, and 20q. Pearson correlations of gene expression profiles of tumors and xenograft passages were above 0.88 for all models. Gene expression patterns between early and late passage xenografts were highly stable for each individual model. Changes observed in xenograft passages largely corresponded to human stromal compartment genes and inflammatory processes. While some differences exist between the primary tumors and corresponding xenografts, the molecular profiles remain stable after extensive passaging. Evidence for stability in molecular characteristics after several rounds of passaging lends confidence to clinical relevance and allows for expansion of models to generate the requisite number of animals required for cohorts used in drug screening and development studies.