The anti-vegf(R) drug discovery legacy: Improving attrition rates by breaking the vicious cycle of angiogenesis in cancer

Resistance to anti-vascular endothelial growth factor (VEGF) molecules causes lack of response and disease recurrence. Acquired resistance develops as a result of genetic/epigenetic changes conferring to the cancer cells a drug resistant phenotype. In addition to tumor cells, tumor endothelial cells also undergo epigenetic modifications involved in resistance to anti-angiogenic therapies. The association of multiple anti-angiogenic molecules or a combination of anti-angiogenic drugs with other treatment regimens have been indicated as alternative therapeutic strategies to overcome resistance to anti-angiogenic therapies. Alternative mechanisms of tumor vasculature, including intussusceptive microvascular growth (IMG), vasculogenic mimicry, and vascular co-option, are involved in resistance to anti-angiogenic therapies. The crosstalk between angiogenesis and immune cells explains the efficacy of combining anti-angiogenic drugs with immune check-point inhibitors. Collectively, in order to increase clinical benefits and overcome resistance to anti-angiogenesis therapies, pan-omics profiling is key

A comprehensive biological and clinical perspective can drive a patient-tailored approach to multiple myeloma: Bridging the gaps between the plasma cell and the neoplastic niche

There is a broad spectrum of diseases labeled as multiple myeloma (MM). This is due not only to the composite prognostic risk factors leading to different clinical outcomes and responses to treatments but also to the composite tumor microenvironment that is involved in a vicious cycle with the MM plasma cells. New therapeutic strategies have improved MM patients' chances of survival. Nevertheless, certain patients' subgroups have a particularly unfavorable prognosis. Biological stratification can be subdivided into patient, disease, or therapy-related factors. Alternatively, the biological signature of aggressive disease and dismal therapeutic response can promote a dynamic, comprehensive strategic approach, better tailoring the clinical management of highrisk profiles and refractoriness to therapy and taking into account the role played by the MM milieu. By means of an extensive literature search, we have reviewed the state-of-the-art pathophysiological insights obtained from translational investigations of the MM-bone marrow microenvironment. A good knowledge of the MM niche pathophysiological dissection is crucial to tailor personalized approaches in a bench-bedside fashion. The discussion in this review pinpoints two main aspects that appear fundamental in order to gain novel and definitive results from the biology of MM. A systematic knowledge of the plasma cell disorder, along with greater efforts to face the unmet needs present in MM evolution, promises to open a new therapeutic window looking out onto the plethora of scientific evidence about the myeloma and the bystander cells

Removal and fate of pesticides in a farm constructed wetland for agricultural drainage water treatment under Mediterranean conditions (Italy)

A non-waterproofed surface flow constructed wetland (SFCW), treating agricultural drainage water in Northern Italy, was investigated to gain information on the potential ability for effective pesticide abatement. A mixture of insecticide imidacloprid, fungicide dimethomorph, and herbicide glyphosate was applied, by simulating a single rain event, into 470-m-long water course of the SFCW meanders. The pesticides were monitored in the wetland water and soil for about 2 months after treatment. Even though the distribution of pesticides in the wetland was not uniform, for each of them, a mean dissipation of 50% of the applied amount was already observed at ≤7 days. The dissipation trend in the water phase of the wetland fitted (r2 ≥ 0.8166) the first-order model with calculated DT50 of 20.6, 12.0, 5.8, and 36.7 days for imidacloprid, dimethomorph, glyphosate, and the glyphosate metabolite AMPA, respectively. The pesticide behavior was interpreted based on the chemical and physical characteristics of both the substances and the water-soil system. Despite the fast abatement of glyphosate, traces were detected in the water until the end of the trial. The formation of soluble 1:1 complex between glyphosate and calcium, the most representative cation in the wetland water, was highlighted by infrared analyses. Such a soluble complex was supposed to keep traces of the herbicide in solution

The Cosmic-ray Soil Moisture Observation System (Cosmos) for estimating the crop water requirement: new approach

Soil moisture is a crucial parameter to determine the crop water requirement for irrigation. The soil moisture deficit (SMD) of the root zone is an indicator that can be used to determine the exact crop water requirement. Application of the recent technology of COsmic-ray Soil Moisture Observation System (Cosmos) provides continuous, integrated, area-based values, with a measurement radius of up to 400 m, whilst being non-invasive. In a field experiment in Italy, the Cosmos probe was used over a mixed crop area during the cropping seasons of 2014 and 2015. The results showed that soil moisture values obtained by Cosmos were comparable with those obtained for the top 0–60 cm layer soil moisture measured by sensors, soil cores, profile probes and with values simulated by the SALTMED model. This indicates that the Cosmos probe's effective depth of sensing is within the top 0–60 cm. Knowing that almost 80% of the crop root system is accommodated within the top 0–60 cm, the Cosmos measurement could be useful for monitoring the soil water status and SMD in the root zone in irrigated agriculture. The Cosmos system could be made operational for irrigation managers to determine when and how much to irrigat

Towards accurate estimation of crop water requirement without the crop coefficient Kc: new approach using modern technologies

Modern technologies to measure actual evapotranspiration, ETa, were implemented at an experimental farm near Bologna, Italy. Large-aperture scintillometer and eddy covariance instruments were installed. The results showed significant differences between actual evapotranspiration measured by eddy covariance and scintillometer when compared with the potential reference evapotranspiration, ET0, calculated from meteorological data using the Penman–Monteith equation and the crop potential evapotranspiration, ETc, which is based on the ET0 and the crop coefficient, Kc. The ETc and ET0 showed higher values than those of ETa obtained by eddy covariance and scintillometer. On average the actual evapotranspiration measured by eddy covariance and scintillometer for the cropping seasons 2014 and 2015 represented 45 and 35% of the ET0 or the ETc, respectively. The ET0, or the ETc, represent the atmospheric water demand while, fundamentally, the crop water requirement should be based on crop water demand better represented by the actual evapotranspiration. At present, the results indicate that the actual crop water requirement based on modern technologies could save at least 50% of irrigation water for this region. Another benefit is that these modern technologies do not need the crop coefficient Kc, which for many irrigation practitioners is difficult to obtain

Pancreatic cancer signaling pathways, genetic alterations, and tumor microenvironment: The barriers affecting the method of treatment

Genetic alterations, especially the K-Ras mutation, carry the heaviest burden in the progression of pancreatic precursor lesions into pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment is one of the challenges that hinder the therapeutic approaches from functioning sufficiently and leads to the immune evasion of pancreatic malignant cells. Mastering the mechanisms of these two hallmarks of PDAC can help us in dealing with the obstacles in the way of treatment. In this review, we have analyzed the signaling pathways involved in PDAC development and the immune system’s role in pancreatic cancer and immune checkpoint inhibition as next-generation therapeutic strategy. The direct targeting of the involved signaling molecules and the immune checkpoint molecules, along with a combination with conventional therapies, have reached the most promising results in pancreatic cancer treatment

The highly conserved nuclear lamin Ig-fold binds to PCNA: its role in DNA replication

This study provides insights into the role of nuclear lamins in DNA replication. Our data demonstrate that the Ig-fold motif located in the lamin C terminus binds directly to proliferating cell nuclear antigen (PCNA), the processivity factor necessary for the chain elongation phase of DNA replication. We find that the introduction of a mutation in the Ig-fold, which alters its structure and causes human muscular dystrophy, inhibits PCNA binding. Studies of nuclear assembly and DNA replication show that lamins, PCNA, and chromatin are closely associated in situ. Exposure of replicating nuclei to an excess of the lamin domain containing the Ig-fold inhibits DNA replication in a concentration-dependent fashion. This inhibitory effect is significantly diminished in nuclei exposed to the same domain bearing the Ig-fold mutation. Using the crystal structures of the lamin Ig-fold and PCNA, molecular docking simulations suggest probable interaction sites. These findings also provide insights into the mechanisms underlying the numerous disease-causing mutations located within the lamin Ig-fold