The role of autophagy in osteoclast differentiation and bone resorption function

Autophagy is an evolutionary conserved and highly regulated recycling process of cellular wastes. Having a housekeeping role, autophagy through the digestion of domestic cytosolic organelles, proteins, macromolecules, and pathogens, eliminates unnecessary materials and provides nutrients and energy for cell survival and maintenance. The critical role of autophagy and autophagy-related proteins in osteoclast differentiation, bone resorption, and maintenance of bone homeostasis has previously been reported. Increasing evidence reveals that autophagy dysregulation leads to alteration of osteoclast function and enhanced bone loss, which is associated with the onset and progression of osteoporosis. In this review, we briefly consolidate the current state-of-the-art technology regarding the role of autophagy in osteoclast function in both physiologic and pathologic conditions to have a more general view on this issue

Quantifying and Maximising the Benefits of Crops After Rice

At the time this project was conceived, rising watertables and subsequent salinisation were considered to be the major threats to the sustainability of irrigated agriculture in the rice growing areas of southern NSW. The biggest threat to sustainability at present is the reduced availability and higher cost of water as a result of the water reforms, and more recently prolonged drought. The hypothesis of this project was that growing crops immediately after rice would increase water use efficiency and profitability of rice-based cropping systems while reducing net recharge. Field experiments were conducted from 1998 to 2000 on two soil types to evaluate the effect of non-irrigated wheat after rice on watertables and net recharge. Rainfall during the wheat season was reasonably similar in all 3 years (270-318 mm) and higher than average (220 mm). Yield and biomass production of early sown (24 April) wheat were higher than yield of late wheat (29 June) (grain yield 4.7 vs 3.8 t/ha at 12% moisture). In the absence of irrigation, the soil profile remained wet in fallow areas, whereas there was considerable drying in areas planted to wheat. The drying created capacity in the soil profile to capture and use winter rainfall. There was a general increase in depth to the watertable during the first half of the season where non-irrigated wheat was grown after rice, but not in the fallow areas. However, in all situations, the watertable rose around the time of rice sowing each year due to a rise in the regional groundwater level. The lumped water balance studies suggested net discharge of about 1 ML/ha between the time of sowing and harvesting wheat after rice in each of the three years, mostly due to higher upflow due to crop water use. In the fallow, net discharge/recharge was close to zero. The CERES Wheat and SWAGMAN® Destiny models performed very well in simulating a wide range of crop and soil water parameters, although the validation data sets were limited in that the yield range was smaller than desirable. Consistent with the field studies, yield of nonirrigated early sown wheat (median 3.8 t/ha) was usually much higher than yield of late sown wheat (median 1.8 t/ha). With one or two irrigations yields of both early and late sown wheat almost always increased, by around 1 t/ha with one irrigation at heading, and an additional 0.5 t/ha with a second irrigation during grain filling. It was only with frequent irrigation (whenever cumulative ETo-rain since the previous irrigation reached 60 mm) that yields of late sown wheat matched (or surpassed) yields of early sown wheat. However, the irrigation requirement for late wheat irrigated at ETo-rain 60 mm was almost always much higher than for early wheat with the same irrigation management (by >100 mm in most years). While irrigation increased yield, it also increased net recharge, with final watertables generally higher by 0.5 to 0.8 m for wheat after rice (wet initial soil) with irrigation at ETo-rain 60 mm compared with no irrigation. The model simulations showed that with wheat after rice, there was net discharge in almost all years, regardless of initial watertable depth (0.5-1.5 m). In comparison, net recharge occurred in 18 to 48% of years with fallow after rice, the amount of recharge increase as initial depth to the watertable increased. For non-irrigated wheat after rice, salinity of the watertable was 2 important where the watertable was shallow (0.5 m), with yield reductions in excess of 1 t/ha in most years. However for deeper watertables, there was no effect of watertable salinity for non-irrigated wheat. With irrigation, watertable salinity had no impact on yields. Growing wheat immediately after rice was financially beneficial, with an increase in Net Present Value (NPV) ranging from 31 to 126 $/ha/yr depending on the rotation. Assuming that the rate of adoption is doubled over 20 years as a result of the project, the NPV of benefits was estimated to be$5.6 million compared with costs of $1.1 million, resulting in a benefit cost ratio of 5.3

Quantifying and Maximising the Benefits of Crops After Rice

At the time this project was conceived, rising watertables and subsequent salinisation were considered to be the major threats to the sustainability of irrigated agriculture in the rice growing areas of southern NSW. The biggest threat to sustainability at present is the reduced availability and higher cost of water as a result of the water reforms, and more recently prolonged drought. The hypothesis of this project was that growing crops immediately after rice would increase water use efficiency and profitability of rice-based cropping systems while reducing net recharge. Field experiments were conducted from 1998 to 2000 on two soil types to evaluate the effect of non-irrigated wheat after rice on watertables and net recharge. Rainfall during the wheat season was reasonably similar in all 3 years (270-318 mm) and higher than average (220 mm). Yield and biomass production of early sown (24 April) wheat were higher than yield of late wheat (29 June) (grain yield 4.7 vs 3.8 t/ha at 12% moisture). In the absence of irrigation, the soil profile remained wet in fallow areas, whereas there was considerable drying in areas planted to wheat. The drying created capacity in the soil profile to capture and use winter rainfall. There was a general increase in depth to the watertable during the first half of the season where non-irrigated wheat was grown after rice, but not in the fallow areas. However, in all situations, the watertable rose around the time of rice sowing each year due to a rise in the regional groundwater level. The lumped water balance studies suggested net discharge of about 1 ML/ha between the time of sowing and harvesting wheat after rice in each of the three years, mostly due to higher upflow due to crop water use. In the fallow, net discharge/recharge was close to zero. The CERES Wheat and SWAGMAN® Destiny models performed very well in simulating a wide range of crop and soil water parameters, although the validation data sets were limited in that the yield range was smaller than desirable. Consistent with the field studies, yield of nonirrigated early sown wheat (median 3.8 t/ha) was usually much higher than yield of late sown wheat (median 1.8 t/ha). With one or two irrigations yields of both early and late sown wheat almost always increased, by around 1 t/ha with one irrigation at heading, and an additional 0.5 t/ha with a second irrigation during grain filling. It was only with frequent irrigation (whenever cumulative ETo-rain since the previous irrigation reached 60 mm) that yields of late sown wheat matched (or surpassed) yields of early sown wheat. However, the irrigation requirement for late wheat irrigated at ETo-rain 60 mm was almost always much higher than for early wheat with the same irrigation management (by >100 mm in most years). While irrigation increased yield, it also increased net recharge, with final watertables generally higher by 0.5 to 0.8 m for wheat after rice (wet initial soil) with irrigation at ETo-rain 60 mm compared with no irrigation. The model simulations showed that with wheat after rice, there was net discharge in almost all years, regardless of initial watertable depth (0.5-1.5 m). In comparison, net recharge occurred in 18 to 48% of years with fallow after rice, the amount of recharge increase as initial depth to the watertable increased. For non-irrigated wheat after rice, salinity of the watertable was 2 important where the watertable was shallow (0.5 m), with yield reductions in excess of 1 t/ha in most years. However for deeper watertables, there was no effect of watertable salinity for non-irrigated wheat. With irrigation, watertable salinity had no impact on yields. Growing wheat immediately after rice was financially beneficial, with an increase in Net Present Value (NPV) ranging from 31 to 126 $/ha/yr depending on the rotation. Assuming that the rate of adoption is doubled over 20 years as a result of the project, the NPV of benefits was estimated to be$5.6 million compared with costs of $1.1 million, resulting in a benefit cost ratio of 5.3

The promise of liquid biopsy to predict response to immunotherapy in metastatic melanoma

Metastatic melanoma is the deadliest form of skin cancer whose incidence has been rising dramatically over the last few decades. Nowadays, the most successful approach in treating advanced melanoma is immunotherapy which encompasses the use of immune checkpoint blockers able to unleash the immune system’s activity against tumor cells. Immunotherapy has dramatically changed clinical practice by contributing to increasing long term overall survival. Despite these striking therapeutic effects, the clinical benefits are strongly mitigated by innate or acquired resistance. In this context, it is of utmost importance to develop methods capable of predicting patient response to immunotherapy. To this purpose, one major step forward may be provided by measuring non-invasive biomarkers in human fluids, namely Liquid Biopsies (LBs). Several LB approaches have been developed over the last few years thanks to technological breakthroughs that have allowed to evaluate circulating components also when they are present in low abundance. The elements of this so-called “circulome” mostly encompass: tumor DNA, tumor and immune cells, soluble factors and non-coding RNAs. Here, we review the current knowledge of these molecules as predictors of response to immunotherapy in metastatic melanoma and predict that LB will soon enter into routine practice in order to guide clinical decisions for cancer immunotherapy

Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas. effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization

Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy. Video Abstract

Comparing the hierarchy of keywords in on-line news portals

The tagging of on-line content with informative keywords is a widespread phenomenon from scientific article repositories through blogs to on-line news portals. In most of the cases, the tags on a given item are free words chosen by the authors independently. Therefore, relations among keywords in a collection of news items is unknown. However, in most cases the topics and concepts described by these keywords are forming a latent hierarchy, with the more general topics and categories at the top, and more specialised ones at the bottom. Here we apply a recent, cooccurrence-based tag hierarchy extraction method to sets of keywords obtained from four different on-line news portals. The resulting hierarchies show substantial differences not just in the topics rendered as important (being at the top of the hierarchy) or of less interest (categorised low in the hierarchy), but also in the underlying network structure. This reveals discrepancies between the plausible keyword association frameworks in the studied news portals

Sex Differences in Cannabinoid 1 vs. Cannabinoid 2 Receptor-Selective Antagonism of Antinociception Produced by Δ 9

The purpose of this study was to determine whether sex differ-ences in cannabinoid (CB)-induced antinociception and motoric effects can be attributed to differential activation of CB1 or CB2 receptors. Rats were injected intraperitoneally with vehicle, rimon-abant [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (SR141716A), a putative CB1 receptor-selective antagonist; 0.1–10 mg/kg] or 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528) (a putative CB2 receptor-selective antagonist; 1.0–10 mg/kg). Thirty minutes later, 9-tetrahydrocannabinol (THC; 1.25–40 mg/kg) or 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol (CP55,940) (0.05–1.6 mg/kg) was injected. Paw pressure and tail withdrawal antinociception

Cyclin-Dependent Kinase 4/6 Inhibitors and Dermatologic Adverse Events: Results from the EADV Task Force "Dermatology for Cancer Patients"

Treatment with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with endocrine therapies. However, limited data exists on its cutaneous adverse events (AE). The aim of our retrospective study was to investigate the prevalence, types and management of cutaneous AE during CDK4/6i. 79 adult advanced breast cancer patients affected by 125 skin adverse events during treatment with CDK4/6i were recruited at eleven centers. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and ec-zematous lesions (24/79). We showed that skin reactions are usually mild in severity, and prompt management may limit the negative impact on patients, facilitating beneficial continuation of oncologic treatment