With future climatic scenarios foreseeing increased crop water demands and reduced irrigation water availability, a deeper knowledge on the dynamics of water uptake and translocation inside plants is ...needed. Little is known about the time interval existing between the irrigation water supply and the presence of irrigation water inside trees, and whether the dripper localization can affect water uptake and translocation dynamics. Another research gap concerns the redistribution of irrigation water in the canopy following irrigation localized to one side of the tree.
A field and a pot experiment were designed to gain more insight into this context. In the field experiment, we tested the effect of different drip irrigation layouts on the extent and velocity of water uptake by apple trees. Trees were irrigated using deuterium-enriched water using one, two, or four drippers per tree. Samples were collected from different heights in the canopy at regular intervals following the irrigation event. In the pot experiment, the soil was saturated with labelled water and samples were collected at different time intervals and heights along the tree stem. Labelled water was detected in the lowest stem section of potted trees after 1 h from irrigation. In field-grown trees, labelled water appeared in the shoots after 4 h and 6 h in the bottom and top part of the canopy, respectively. By increasing the number of drippers per tree, the fraction of irrigation water in the shoots increased accordingly. However, uptake and transport velocity were unaffected by the number of drippers, averaging 0.60–0.65 m h-1. In trees that were irrigated from one side only, irrigation water could be found on the opposite side in the top part of the canopy. Our results suggest that the localization and amount of irrigation water can significantly influence root water uptake in apple trees.
•Under field conditions irrigation water was detected in the shoots 4 h after supply.•Increasing the number of drippers and irrigation water amount enhanced water uptake.•Locally-absorbed water moves radially across the stem and reaches the entire canopy.
Age estimation from radiologic data is an important topic both in clinical medicine as well as in forensic applications, where it is used to assess unknown chronological age or to discriminate minors ...from adults. In this paper, we propose an automatic multi-factorial age estimation method based on MRI data of hand, clavicle, and teeth to extend the maximal age range from up to 19 years, as commonly used for age assessment based on hand bones, to up to 25 years, when combined with clavicle bones and wisdom teeth. Fusing age-relevant information from all three anatomical sites, our method utilizes a deep convolutional neural network that is trained on a dataset of 322 subjects in the age range between 13 and 25 years, to achieve a mean absolute prediction error in regressing chronological age of <inline-formula><tex-math notation="LaTeX">1.01\pm 0.74</tex-math></inline-formula> years. Furthermore, when used for majority age classification, we show that a classifier derived from thresholding our regression-based predictor is better suited than a classifier directly trained with a classification loss, especially when taking into account that those cases of minors being wrongly classified as adults need to be minimized. In conclusion, we overcome the limitations of the multi-factorial methods currently used in forensic practice, i.e., dependence on ionizing radiation, subjectivity in quantifying age-relevant information, and lack of an established approach to fuse this information from individual anatomical sites.
Multiple Myeloma (MM) is a hematological cancer characterized by proliferation of malignant plasma cells in the bone marrow (BM). MM represents the second most frequent hematological malignancy, ...accounting 1% of all cancer and 13% of hematological tumors, with ~9,000 new cases per year. Patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic smoldering MM (SMM) usually evolve to active MM in the presence of increased tumor burden, symptoms and organ damage. Despite the role of high dose chemotherapy in combination with autologous stem cell transplantation and the introduction of new treatments, the prognosis of MM patients is still poor, and novel therapeutic approaches have been tested in the last years, including new immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies (mAbs). CD38 is a glycoprotein with ectoenzymatic functions, which is expressed on plasma cells and other lymphoid and myeloid cell populations. Since its expression is very high and uniform on myeloma cells, CD38 is a good target for novel therapeutic strategies. Among them, immunotherapy represents a promising approach. Here, we summarized recent findings regarding CD38-targeted immunotherapy of MM in pre-clinical models and clinical trials, including (i) mAbs (daratumumab and isatuximab), (ii) radioimmunotherapy, and (iii) adoptive cell therapy, using chimeric antigen receptor (CAR)-transfected T cells specific for CD38. Finally, we discussed the efficacy and possible limitations of these therapeutic approaches for MM patients.
Multiple myeloma (MM) is a clonal plasma cell malignancy associated with osteolytic bone disease. Recently, the role of MM-derived exosomes in the osteoclastogenesis has been demonstrated although ...the underlying mechanism is still unknown. Since exosomes-derived epidermal growth factor receptor ligands (EGFR) are involved in tumor-associated osteolysis, we hypothesize that the EGFR ligand amphiregulin (AREG) can be delivered by MM-derived exosomes and participate in MM-induced osteoclastogenesis.
Exosomes were isolated from the conditioned medium of MM1.S cell line and from bone marrow (BM) plasma samples of MM patients. The murine cell line RAW264.7 and primary human CD14
cells were used as osteoclast (OC) sources.
We found that AREG was specifically enriched in exosomes from MM samples and that exosomes-derived AREG led to the activation of EGFR in pre-OC, as showed by the increase of mRNA expression of its downstream SNAIL in both RAW264.7 and CD14
cells. The presence of neutralizing anti-AREG monoclonal antibody (mAb) reverted this effect. Consequently, we showed that the effect of MM-derived exosomes on osteoclast differentiation was inhibited by the pre-treatment of exosomes with anti-AREG mAb. In addition, we demonstrated the ability of MM-derived AREG-enriched exosomes to be internalized into human mesenchymal stromal cells (MSCs) blocking osteoblast (OB) differentiation, increasing MM cell adhesion and the release of the pro-osteoclastogenic cytokine interleukin-8 (IL8). Accordingly, anti-AREG mAb inhibited the release of IL8 by MSCs suggesting that both direct and indirect effects are responsible for AREG-enriched exosomes involvement on MM-induced osteoclastogenesis.
In conclusion, our data indicate that AREG is packed into MM-derived exosomes and implicated in OC differentiation through an indirect mechanism mediated by OBs.
The study of osteoblast (OB) metabolism has recently received increased attention due to the considerable amount of energy used during the bone remodeling process. In addition to glucose, the main ...nutrient for the osteoblast lineages, recent data highlight the importance of amino acid and fatty acid metabolism in providing the fuel necessary for the proper functioning of OBs. Among the amino acids, it has been reported that OBs are largely dependent on glutamine (Gln) for their differentiation and activity. In this review, we describe the main metabolic pathways governing OBs' fate and functions, both in physiological and pathological malignant conditions. In particular, we focus on multiple myeloma (MM) bone disease, which is characterized by a severe imbalance in OB differentiation due to the presence of malignant plasma cells into the bone microenvironment. Here, we describe the most important metabolic alterations involved in the inhibition of OB formation and activity in MM patients.
Multiple myeloma (MM) is a plasma cell malignancy characterized by a high capacity to induce osteolytic bone lesions. Bone destruction in MM results from increased osteoclast formation and activity ...that occur in close proximity to myeloma cells. However, histomorphometric studies have demonstrated that MM patients with osteolytic bone lesions have lower numbers of osteoblasts and decreased bone formation. This impaired bone formation plays a critical role in the bone-destructive process. Recently, the biologic mechanisms involved in the osteoblast inhibition induced by MM cells have begun to be elucidated. In this article, the pathophysiology underlying osteoblast inhibition in MM is reviewed.
Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of bone marrow (BM) clonal plasma cells, which are strictly dependent on the microenvironment. Despite the ...improvement of MM survival with the use of new drugs, MM patients still relapse and become always refractory to the treatment. The development of new therapeutic strategies targeting both tumor and microenvironment cells are necessary. Oncolytic virotherapy represent a promising approach in cancer treatment due to tumor-specific oncolysis and activation of the immune system. Different types of human viruses were checked in preclinical MM models, and the use of several viruses are currently investigated in clinical trials in MM patients. More recently, the use of alternative non-human viruses has been also highlighted in preclinical studies. This strategy could avoid the antiviral immune response of the patients against human viruses due to vaccination or natural infections, which could invalid the efficiency of virotherapy approach. In this review, we explored the effects of the main oncolytic viruses, which act through both direct and indirect mechanisms targeting myeloma and microenvironment cells inducing an anti-MM response. The efficacy of the oncolytic virus-therapy in combination with other anti-MM drugs targeting the microenvironment has been also discussed.
Osteocytes are terminally differentiated cells of the osteoblast lineage. They are involved in the regulation of bone remodeling by increasing osteoclast formation or decreasing bone formation by the ...secretion of the osteoblast inhibitor sclerostin. Monoclonal antibody anti-sclerostin, Romosozumab, has been developed and tested in clinical trials in patients with osteoporosis. In the last years, the role of osteocytes in the development of osteolytic bone lesions that occurs in multiple myeloma, have been underlined. Myeloma cells increase osteocyte death through the up-regulation of both apoptosis and autophagy that, in turn, triggers osteoclast formation, and activity. When compared to healthy controls, myeloma patients with bone disease have higher osteocyte cell death, but the treatment with proteasome inhibitor bortezomib has been shown to maintain osteocyte viability. In preclinical mouse models of multiple myeloma, treatment with blocking anti-sclerostin antibody increased osteoblast numbers and bone formation rate reducing osteolytic bone lesions. Moreover, the combination of anti-sclerostin antibody and the osteoclast inhibitor zoledronic acid increased bone mass and fracture resistance synergistically. However, anti-sclerostin antibody did not affect tumor burden
or the efficacy of anti-myeloma drugs
. Nevertheless, the combination therapy of anti-sclerostin antibody and the proteasome inhibitor carfilzomib, displayed potent anti-myeloma activity as well as positive effects on bone disease
. In conclusion, all these data suggest that osteocytes are involved in myeloma bone disease and may be considered a novel target for the use of antibody-mediated anti-sclerostin therapy also in multiple myeloma patients.
The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell ...lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138+ cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138+ cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138+ cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.
•Myeloma cells produce ammonium in the presence of glutamine, showing high glutaminase and low glutamine synthetase expression.•Myeloma cells show high expression of glutamine transporters and inhibition of ASCT2 transporter hinders myeloma growth.
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