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BackgroundCoronavirus disease 2019 (COVID-19) is an immunoinflammatory and hypercoagulable state that contributes to respiratory distress, multi-organ dysfunction, and mortality. Dipyridamole, by increasing extracellular adenosine, has been postulated to be protective for COVID-19 patients through its immunosuppressive, anti-inflammatory, anti-coagulant, vasodilatory, and anti-viral actions. Likewise, low-dose aspirin has also demonstrated protective effects for COVID-19 patients. This study evaluated the effect of these two drugs formulated together as Aggrenox in hospitalized COVID-19 patients.MethodsIn an open-label, single site randomized controlled trial (RCT), hospitalized COVID-19 patients were assigned to adjunctive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) with standard of care treatment compared to standard of care treatment alone. Primary endpoint was illness severity according to changes on the eight-point COVID ordinal scale, with levels of 1 to 8 where higher scores represent worse illness. Secondary endpoints included all-cause mortality and respiratory failure. Outcomes were measured through days 14, 28, and/or hospital discharge.ResultsFrom October 1, 2020 to April 30, 2021, a total of 98 patients, who had a median [IQR] age of 57 [47, 62] years and were 53.1% (n = 52) female, were randomized equally between study groups (n = 49 Aggrenox plus standard of care versus n = 49 standard of care alone). No clinically significant differences were found between those who received adjunctive Aggrenox and the control group in terms of illness severity (COVID ordinal scale) at days 14 and 28. The overall mortality through day 28 was 6.1% (3 patients, n = 49) in the Aggrenox group and 10.2% (5 patients, n = 49) in the control group (OR [95% CI]: 0.40 [0.04, 4.01], p = 0.44). Respiratory failure through day 28 occurred in 4 (8.3%, n = 48) patients in the Aggrenox group and 7 (14.6%, n = 48) patients in the standard of care group (OR [95% CI]: 0.21 [0.02, 2.56], p = 0.22). A larger decrease in the platelet count and blood glucose levels, and larger increase in creatinine and sodium levels within the first 7 days of hospital admission were each independent predictors of 28-day mortality (p < 0.05).ConclusionIn this study of hospitalized patients with COVID-19, while the outcomes of COVID illness severity, odds of mortality, and chance of respiratory failure were better in the Aggrenox group compared to standard of care alone, the data did not reach statistical significance to support the standard use of adjuvant Aggrenox in such patients.

This was a two-stage phase II trial of a mTORC1/2 inhibitor (mTORC: mammalian target of rapamycin complex) Sapanisertib (TAK228) in patients with rapalog-resistant pancreatic neuroendocrine tumors (PNETs) (NCT02893930). Approved rapalogs such as everolimus inhibit mTORC1 and have limited clinical activity, possibly due to compensatory feedback loops. Sapanisertib addresses the potential for incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2, and thus to reverse resistance to earlier rapamycin analogues. In stage 1, patients received sapanisertib 3 mg by mouth once daily on a continuous dosing schedule in 28-day cycle. This trial adopted a two-stage design with the primary objective of evaluating objective tumor response. The first stage would recruit 13 patients in order to accrue 12 eligible and treated patients. If among the 12 eligible patients at least 1 patient had an objective response to therapy, the study would move to the second stage of accrual where 25 eligible and treated patients would be enrolled. This study activated on February 1, 2017, the required pre-determined number of patients (n = 13) had entered by November 5, 2018 for the first stage response evaluation. The accrual of this trial was formally terminated on December 27, 2019 as no response had been observed after the first stage accrual. Treatment-related grade 3 adverse events were reported in eight (61%) patients with hyperglycemia being the most frequent, in three patients (23%). Other toxicities noted in the trial included fatigue, rash diarrhea, nausea, and vomiting. The median PFS was 5.19 months (95% CI [3.84, 9.30]) and the median OS was 20.44 months (95% CI [5.65, 22.54]). Due to the lack of responses in Stage 1 of the study, the study did not proceed to stage 2. Thus the potential to reverse resistance was not evident.

Introduction Poststroke spasticity (PSS) affects up to 40% of patients who had a stroke. Botulinum neurotoxin type A (BoNT-A) has been shown to improve spasticity, but the optimal timing of its application remains unclear. While several predictors of upper limb PSS are known, their utility in clinical practice in relation to BoNT-A treatment has yet to be fully elucidated. The COLOSSEO-BoNT study aims to investigate predictors of PSS and the effects of BoNT-A timing on spasticity-related metrics in a real-world setting.Methods and analysis The recruitment will involve approximately 960 patients who have recently experienced an ischaemic stroke (within 10 days, V0) and will follow them up for 24 months. Parameters will be gathered at specific intervals: (V1) 4, (V2) 8, (V3) 12, (V4) 18 months and (V5) 24 months following enrolment. Patients will be monitored throughout their rehabilitation and outpatient clinic journeys and will be compared based on their BoNT-A treatment status—distinguishing between patients receiving treatment at different timings and those who undergo rehabilitation without treatment. Potential predictors will encompass the Fugl-Meyer assessment, the National Institute of Health Stroke Scale (NIHSS), stroke radiological characteristics, performance status, therapies and access to patient care pathways. Outcomes will evaluate muscle stiffness using the modified Ashworth scale and passive range of motion, along with measures of quality of life, pain, and functionality.Ethics and dissemination This study underwent review and approval by the Ethics Committee of the Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. Regardless of the outcome, the findings will be disseminated through publication in peer-reviewed journals and presentations at national and international conferences.Trial registration number NCT05379413.

Chenopodium quinoa Willd. (quinoa), a highly nutritious pseudocereal, is a promising crop to address global food insecurity challenges intensified by population growth and climate change. However, drought stress remains a significant constraint for quinoa cultivation. The plant exhibits several morphophysiological adaptations to water stress conditions, including root system modifications, reduced growth rate, leaf abscission, and stomatal closure. While these adaptations enhance drought tolerance, they can also negatively impact plant growth, potentially through alterations in root architecture, physiological changes, e.g., stomatal regulations, and anatomical changes. Different studies have suggested that soil amendment with biochar, a pyrolyzed organic material, can improve quinoa growth and productivity under drought stress conditions. Biochar application to the soil significantly enhances soil physiochemical characteristics and maintains plant water status, thereby promoting plant growth and potentially mitigating the negative consequences of drought on quinoa production. This review focuses on the current understanding of quinoa behavior under drought stress and the potential of soil amendment with biochar as a management strategy. We summarize existing research on applying biochar-amended soil to alleviate quinoa drought stress.

Drought stress deteriorates agro-ecosystems and poses a significant threat to crop productivity and food security. Soil amended with biochar has been suggested to mitigate water stress, but there is limited knowledge about how biochar affects the physiology and vegetative growth of quinoa plants under soil water deficits. We grew three quinoa (Chenopodium quinoa Willd.) varieties, Titicaca (V1), Quipu (V2), and UAFQ7 (V3) in sandy loam soil without (B0) and with 2% woodchip biochar (B2) under drought conditions. The drought resulted in significant growth differences between the varieties. V3 performed vegetatively better, producing 46% more leaves, 28% more branches, and 25% more leaf area than the other two varieties. Conversely, V2 displayed significantly higher yield-contributing traits, with 16% increment in panicle length and 50% more subpanicles compared to the other varieties. Woodchip biochar application significantly enhanced the root development (i.e., root biomass, length, surface, and projected area) and plant growth (i.e., plant height, leaf area, and absolute growth rate). Biochar significantly enhanced root growth, especially fresh and dry weights, by 122% and 127%, respectively. However, biochar application may lead to a trade-off between vegetative growth and panicle development under drought stress as shown for V3 grown in soil with woodchip biochar. However, V3B2 produced longer roots and more biomass. Collectively, we suggest exploring the effects of woodchip biochar addition to the soil on the varietal physiological responses such as stomatal regulations and mechanisms behind the increased quinoa yield under water stress conditions.

Tomato grafting is an effective practice in increasing the profitability of fresh-market tomato cultivation, especially in greenhouses, and is also considered a strategy for enhancing fruit quality. In this study, selected quanti-qualitative traits, and the of bioactive health-promoting compound and organic acid contents of cherry tomato fruits from three different scion/rootstock combinations (Sunstream/Top Bental, Sunstream/Kaiser and Sunstream/Suzuka) grown under a greenhouse hydroponic system were evaluated in three different harvests (beginning, middle and end of the whole harvesting period) and on three different bunch portions (proximal, central and distal). Although the tomato productive performance was influenced by the rootstock, with Suzuka and Kaiser grafted plants showing the highest total marketable yield (9.8 kg plant−1, i.e., 20% more than Top Bental), the yield-related traits (bunch number, weight and length per plant, and fruit number per bunch) and the qualitative characteristics of the fruits (color, equatorial and polar diameters, dry matter and solid soluble contents, pH and titratable acidity) showed less variability, by displaying, along with the bioactive compound contents (total polyphenols, lycopene, β-carotene), DPPH free radical scavenging activity and organic acids contents (lactic and acetic), a significant effect of the harvesting time and bunch portion. Fruits from the beginning of the harvesting period showed better qualitative and functional properties, with the lycopene and β-carotene contents equal to 178.6 and 3 mg 100 g−1 fw, and fruits from proximal and central bunch portions had lycopene and β-carotene contents equal to 203.1 and 2.9 mg 100 g−1 fw.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

Abstract Head and neck cancer, the sixth most common cancer worldwide, account for about 1 out of 20 malignant tumors. In recent years a reduction in the incidence of cervical cancer, but a concomitant major increase in the incidence of HPV-mediated oropharyngeal cancer caused by orogenital HPV transmission has been observed. Consequently, in wealthy countries oropharyngeal squamous-cell carcinomas (OPSCC) is now the most frequent HPV-related cancer, having overtaken cervical cancer. Without effective medical interventions, this incidence trend could continue for decades. As no specific precursor lesion has been consistently identified in the oral cavity and oropharynx, HPV vaccination is the logical intervention to successfully counteract also the rising incidence of OPSCCs. However, HPV vaccine uptake remains suboptimal, particularly in males, the population at higher risk of OPSCC. Alternative primary prevention measures, such as modifications in sexual behaviors, could be implemented based on knowledge of individual genital HPV status. Until recently, this information was not available at a population level, but the current gradual shift from cytology (Pap test) to primary HPV testing for cervical cancer screening is revealing the presence of oncogenic viral genotypes in millions of women. In the past, health authorities and professional organizations have not consistently recommended modifications in sexual behaviors to be adopted when a persistent high-risk HPV cervicovaginal infection was identified. However, given the above changing epidemiologic scenario and the recent availability of an immense amount of novel information on genital HPV infection, it is unclear whether patient counseling should change. The right of future partners to be informed of the risk could also be considered. However, any modification of the provided counseling should be based also on the actual likelihood of a beneficial effect on the incidence of HPV-associated oropharyngeal cancers. The risk is on one side to induce unjustified anxiety and provide ineffective instructions, on the other side to miss the opportunity to limit the spread of oral HPV infections. Thus, major health authorities and international gynecologic scientific societies should issue or update specific recommendations, also with the aim of preventing inconsistent health care professionals’ behaviors.

The scarcity of water resources is considered a major threat and challenge for agriculture. Water limitations could strongly affect the growth and development of many crops including quinoa, a nutrition-rich, climate-resilient crop that is gaining attention globally. Organic amendment application has been reported as a suitable option to mitigate the detrimental impacts of water shortage on soil and plant growth. In this context, two experiments were conducted on Chenopodium quinoa “Titicaca”; in the first experiment, we investigated the effect of different organic amendments, namely woodchips biochar (Bw), vineyard pruning biochar (Bv), and vermicompost (V), applied (alone and mixed) at 2% soil dry weight, on soil properties and the plant biomass of quinoa subjected to a water stress period during vegetative development. Among organic amendments tested, Bw and Bw+V increased plant biomass on average by 15%, while Bv and Bv+V reduced the plant biomass by 62% compared to non-amended soil (C). A significant reduction in soil pH was observed with Bw (7.61), while BV increased pH (8.04) compared to C (7.76). The Bw and Bv also reduced soil bulk density (BD) (1.19 g/m3 and 1.13 g/m3, respectively) compared to C (1.28 g/m3). As Bw performed better in the first experiment, the second experiment assessed only Bw at different doses, i.e., 0%, 2%, and 4% under water shortage by restoring only 50% evapotranspiration losses, when soil water content reached the 50% of available water content. Considering the Bw rates, the plants treated with Bw2% showed 34% and 19% more biomass and 36% and 66% more panicles than Bw0% and Bw4%, respectively. The Bw2% decreased the soil pH (7.79 versus 7.85) and electrical conductivity (286 versus 307 µS/cm) compared to Bw0%, which was not different from Bw4%. No differences were observed in BD between Bw0% and Bw2% (on average 1.28 g/m3), while BD decreased in Bw4% (1.06 g/m3). The findings of both experiments highlighted that the appropriate type and dose of biochar could improve soil properties and help quinoa plants to grow better under water-limited conditions.

The application of biochar to agricultural soils has been proven to have many advantages, including the improvement of soil water holding capacity and plant growth, particularly under limiting conditions of water supply. The response of quinoa (Chenopodium quinoa Willd.) to water shortage occurring during the vegetative growth stages is not well known. Therefore, the present study aimed to evaluate the combined effects of three wood chip biochar rates (0%, 2% and 4%) and two water regimes (100 and 50% evapotranspiration losses restitution) on the vegetative development and water status of quinoa (cultivar Titicaca). The results showed that the treatment with 2% wood chip biochar improved plant height, leaf and branch number and stem diameter during the vegetative growing cycle compared to the 0% (control) and 4% biochar treatments, which were not different from each other. At the end of the experiment, when the plants were at the flowering initiation stage, increases of 23% in leaf area, 22% in fresh biomass, 27% in main panicle length and 36% in sub-panicle number were observed. The application of woody biochar at a 4% rate, although improving the plant water status with increases of 10% in RWC and 18% in Ψ, did not enhance the vegetative development of the quinoa. The water shortage negatively affected both the growth performance and plant water status. The best growth response of quinoa was observed only when the plants were treated with a 2% biochar rate and were fully irrigated.

BackgroundCoronavirus disease 2019 (COVID-19) is an immunoinflammatory and hypercoagulable state that contributes to respiratory distress, multi-organ dysfunction, and mortality. Dipyridamole, by increasing extracellular adenosine, has been postulated to be protective for COVID-19 patients through its immunosuppressive, anti-inflammatory, anti-coagulant, vasodilatory, and anti-viral actions. Likewise, low-dose aspirin has also demonstrated protective effects for COVID-19 patients. This study evaluated the effect of these two drugs formulated together as Aggrenox in hospitalized COVID-19 patients.MethodsIn an open-label, single site randomized controlled trial (RCT), hospitalized COVID-19 patients were assigned to adjunctive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) with standard of care treatment compared to standard of care treatment alone. Primary endpoint was illness severity according to changes on the eight-point COVID ordinal scale, with levels of 1 to 8 where higher scores represent worse illness. Secondary endpoints included all-cause mortality and respiratory failure. Outcomes were measured through days 14, 28, and/or hospital discharge.ResultsFrom October 1, 2020 to April 30, 2021, a total of 98 patients, who had a median [IQR] age of 57 [47, 62] years and were 53.1% (n = 52) female, were randomized equally between study groups (n = 49 Aggrenox plus standard of care versus n = 49 standard of care alone). No clinically significant differences were found between those who received adjunctive Aggrenox and the control group in terms of illness severity (COVID ordinal scale) at days 14 and 28. The overall mortality through day 28 was 6.1% (3 patients, n = 49) in the Aggrenox group and 10.2% (5 patients, n = 49) in the control group (OR [95% CI]: 0.40 [0.04, 4.01], p = 0.44). Respiratory failure through day 28 occurred in 4 (8.3%, n = 48) patients in the Aggrenox group and 7 (14.6%, n = 48) patients in the standard of care group (OR [95% CI]: 0.21 [0.02, 2.56], p = 0.22). A larger decrease in the platelet count and blood glucose levels, and larger increase in creatinine and sodium levels within the first 7 days of hospital admission were each independent predictors of 28-day mortality (p < 0.05).ConclusionIn this study of hospitalized patients with COVID-19, while the outcomes of COVID illness severity, odds of mortality, and chance of respiratory failure were better in the Aggrenox group compared to standard of care alone, the data did not reach statistical significance to support the standard use of adjuvant Aggrenox in such patients.

Lessons learnedTreatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents.BackgroundThis phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy.MethodsPatients with advanced pNET were randomized (1:1) to oral BEZ235 400 mg twice daily or oral everolimus 10 mg once daily on a continuous dosing schedule. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), and time to treatment failure.ResultsEnrollment in this study was terminated early (62 enrolled of the 140 planned). The median PFS was 8.2 months (95% confidence interval [CI]: 5.3 to not evaluable [NE]) with BEZ235 versus 10.8 months (95% CI: 8.1-NE) with everolimus (hazard ratio 1.53; 95% CI: 0.72-3.25). The most commonly reported all-grade adverse events (>50% of patients regardless of study treatment relationship) with BEZ235 were diarrhea (90.3%), stomatitis (74.2%), and nausea (54.8%).ConclusionBEZ235 treatment in mTOR inhibitor-naïve patients with advanced pNET did not demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.

Low-grade chronic inflammation (LGCI) is a common feature of non-communicable diseases. Cytokines play a crucial role in LGCI. This study aimed to assess how LGCI risk factors [e.g., age, body mass index (BMI), smoke, physical activity, and diet] may impact on specific cytokine levels in a healthy population. In total, 150 healthy volunteers were recruited and subjected to questionnaires about the last 7-day lifestyle, including smoking habit, physical activity, and food frequency. A panel of circulating cytokines, chemokines, and growth factors was analyzed by multiplex ELISA. BMI showed the heaviest impact on the correlation between LGCI-related risk factors and cytokines and was significantly associated with CRP levels. Aging was characterized by an increase in IL-1b, eotaxin, MCP-1, and MIP-1α. Smoking was related to higher levels of IL-1b and CCL5/RANTES, while physical activity was related to MIP-1α. Within the different eating habits, CRP levels were modulated by eggs, red meat, shelled fruits, and greens consumption; however, these associations were not confirmed in a multivariate model after adjusting for BMI. Nevertheless, red meat consumption was associated with an inflammatory pattern, characterized by an increase in IL-6 and IL-8. IL-8 levels were also increased with the frequent intake of sweets, while a higher intake of shelled fruits correlated with lower levels of IL-6. Moreover, IL-6 and IL-8 formed a cluster that also included IL-1b and TNF-α. In conclusion, age, BMI, smoke, physical activity, and dietary habits are associated with specific cytokines that may represent potential markers for LGCI.

While the biomarkers of COVID-19 severity have been thoroughly investigated, the key biological dynamics associated with COVID-19 resolution are still insufficiently understood. We report a case of full resolution of severe COVID-19 due to convalescent plasma transfusion. Following transfusion, the patient showed fever remission, improved respiratory status, and rapidly decreased viral burden in respiratory fluids and SARS-CoV-2 RNAemia. Longitudinal unbiased proteomic analysis of plasma and single-cell transcriptomics of peripheral blood cells conducted prior to and at multiple times after convalescent plasma transfusion identified the key biological processes associated with the transition from severe disease to disease-free state. These included (i) temporally ordered upward and downward changes in plasma proteins reestablishing homeostasis and (ii) post-transfusion disappearance of a subset of monocytes characterized by hyperactivated Interferon responses and decreased TNF-α signaling. Monitoring specific dysfunctional myeloid cell subsets in peripheral blood may provide prognostic keys in COVID-19.

Amino Acids are not only major nutrient sources, but also serve as chemical signals to control cellular growth. Rab1A recently emerged as a key component in amino acid sensing and signaling to activate the mTOR complex1 (mTORC1). In a recently published study [1], we generated tamoxifen-inducible, conditional whole-body Rab1A knockout in adult mice. These mice are viable but develop hyperglycemia and glucose intolerance. Interestingly, Rab1A ablation selectively reduces insulin expression and pancreatic beta-cell population. Mechanistically, branched chain amino acids (BCAA), through the Rab1A-mTORC1 complex, promote the stability and nuclear localization of Pdx1, a master transcription factor that controls growth, function and identity of pancreatic beta-cells. These findings reveal a role and underlying mechanism by which amino acids control body’s glucose level through a beta-cell specific function by the Rab1A-mTORC1-Pdx1 signaling axis, which has implications in both diabetes and cancer.

Prolonged drought periods, increasingly occurring worldwide due to global climate change, could affect the growth and productivity of both traditional and climate-resilient crops, including quinoa. Specifically, the vegetative growing cycle of this species is highly sensitive to drought conditions. In this context, using organic amendments could help plants cope with drought due to their ability to enhance soil water status. So, the current study aimed to investigate the effect of different organic amendments, i.e., two biochars (from woodchips and vineyard prunings) and a vermicompost (from cattle manure), applied to the soil alone and mixed at 2% rate (w/w), on the vegetative development of quinoa (cv. Titicaca), during which a period of water stress was imposed from the twelve-leaf stage to the bud stage. A set of growth-related parameters were measured both during and at the end of the experiment, along with a set of water-related parameters, at the end of the water-stress period and after soil re-watering. The results showed that woodchip biochar, both alone and mixed with vermicompost, significantly affected plant growth during the water-stress period, also allowing a quicker recovery once drought conditions ended. Indeed, the leaf number and area, SPAD index, leaf and stem fresh weight, and dry matter content in plants treated with woodchip biochar, alone and mixed with vermicompost, were higher than vineyard pruning biochar, alone and mixed with vermicompost and similar to the well-watered control plants. Similar results were observed considering the yield contributing traits detected at the end of the experiment, including the main panicle length, number of sub-panicle, as well as fresh weight and dry matter content of both panicle and sub-panicles. Additionally, the water-related parameters, especially the low turgid weight to dry weight ratio of woodchip biochar treated plants, showed evidence of better growth than vineyard pruning biochar. At the end of the experiment, the WUE of plants treated with woodchip biochar and vermicompost, both alone and mixed, was higher than vineyard pruning biochar alone and mixed with vermicompost. Among the tested organic amendments, woodchip biochar alone and mixed with vermicompost positively affected the vegetative growth response of quinoa under water-stress conditions.

Insulinomas are rare, benign beta cell tumours which overproduce insulin and have been associated to epigenetic alterations. Here the authors characterise insulinoma methylomes, finding changes in promoter methylation and chromatin structure proposed to drive the pathological expression of insulin.

As ACE2 is the critical SARS-CoV-2 receptor, we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung, and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here, after demonstrating in vitro neutralization of SARS-CoV-2 by APN01, and after obtaining preliminary evidence of its tolerability and preventive efficacy in a mouse model, we pursued development of an aerosol formulation. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers has now been initiated (NCT05065645), with subsequent Phase II testing planned for individuals with SARS-CoV-2 infection.

This study evaluates the effect of a chemical fertilizer (ammonium nitrate), a compost (vermicompost from cattle manure) and two biochars (from vine prunings and wood chips, respectively), applied to the soil alone or in mixture, on the yield, phytochemical content and biological activity of Beta vulgaris L. var. cycla (Swiss chard). The respective treatments, each replicated four times, were arranged according to a completely randomized block design. Results showed that vermicompost, both alone and in mixture with vine pruning biochar, significantly increased yield parameters (plant height and leaf area) and yield over the untreated soil and the biochars alone, similar to ammonium nitrate. Moreover, vermicompost, both alone and in mixture, respectively, with the two biochars, determined lower total N and NO3− contents than ammonium nitrate, both alone and in mixture, respectively, with the two biochars. In particular, NO3− content was within the safe thresholds fixed for leafy vegetables by the European Commission to prevent any adverse implication on human health from dietary NO3− exposure. The biochars alone resulted in very low yield and leaf total N content, likely due to a limited release of N for plant uptake, also evidenced by the undetectable NO3− leaf content, similarly shown by plants grown in untreated soil. Vermicompost, alone or in mixture, respectively, with the two biochars, increased the content of specialized metabolites, with a positive effect on antioxidant activity. The organic amendments, particularly compost, could be an alternative to chemical fertilizers to reach a trade-off between yield, nutritional and health qualities in Swiss chard, meeting the needs of farmers and consumers as well as the targets for sustainable food production.

BackgroundLate-stage diagnosis of ovarian cancer, a disease that originates in the ovaries and spreads to the peritoneal cavity, lowers 5-year survival rate from 90% to 30%. Early screening tools that can: i) detect with high specificity and sensitivity before conventional tools such as transvaginal ultrasound and CA-125, ii) use non-invasive sampling methods and iii) longitudinally significantly increase survival rates in ovarian cancer are needed. Studies that employ blood-based screening tools using circulating tumor-cells, -DNA, and most recently tumor-derived small extracellular vesicles (sEVs) have shown promise in non-invasive detection of cancer before standard of care. Our findings in this study show the promise of a sEV-derived signature as a non-invasive longitudinal screening tool in ovarian cancer.MethodsHuman serum samples as well as plasma and ascites from a mouse model of ovarian cancer were collected at various disease stages. Small extracellular vesicles (sEVs) were extracted using a commercially available kit. RNA was isolated from lysed sEVs, and quantitative RT-PCR was performed to identify specific metastatic gene expression.ConclusionThis paper highlights the potential of sEVs in monitoring ovarian cancer progression and metastatic development. We identified a 7-gene panel in sEVs derived from plasma, serum, and ascites that overlapped with an established metastatic ovarian carcinoma signature. We found the 7-gene panel to be differentially expressed with tumor development and metastatic spread in a mouse model of ovarian cancer. The most notable finding was a significant change in the ascites-derived sEV gene signature that overlapped with that of the plasma-derived sEV signature at varying stages of disease progression. While there were quantifiable changes in genes from the 7-gene panel in serum-derived sEVs from ovarian cancer patients, we were unable to establish a definitive signature due to low sample number. Taken together our findings show that differential expression of metastatic genes derived from circulating sEVs present a minimally invasive screening tool for ovarian cancer detection and longitudinal monitoring of molecular changes associated with progression and metastatic spread.

Background: Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies. Methods: Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor-immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. Results: The derived parameters Λ and µ were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology. Conclusions: These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis. Funding: We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

From the perspective of sustainable agri-food production, farmers need to make the best use of natural resources. Biochar can be a solution to adopt a more sustainable way of farming. Despite its environmental and agronomic advantages, biochar has a low plant nutrient value. This study evaluated the effect of biochar and the co-application of an inorganic or organic fertilizer on the soil properties, growth and nutrient content of Swiss chard (Beta vulgaris L. var. cycla, Caryophyllales order, Chenopodiaceae family). The experiment consisted of two factors: biochar type (from vineyard prunings and wood chips) and fertilizing source (ammonium nitrate and vermicompost). Biochars were applied at a 2% rate (w/w) and fertilizers at a dose providing 280 kg N ha−1. The soil properties (pH, EC, extractable anions, cations, total N, Corg and C/N ratio) were measured before the plants were transplanted and at the end of the growing cycle, along with the growth parameters (leaf number, length and fresh weight) of each leaf cut, the productive parameters (total number of leaves and yield per plant) at the end of the growing cycle and the leaf content of anions (NO3−, P2O43−, SO42−), cations (NH4+, Na+, K+, Ca2+, Mg2+) and total N. The co-application of biochar and a fertilizing source had a positive effect on soil properties and leaf nutrient content. Vermicompost increased plant growth by 22% and plant yield by 116%, in contrast to biochar, and increased limited leaf NO3− accumulation by about 81% in comparison to ammonium nitrate. The co-application of biochar and vermicompost is the better option to increase Swiss chard yield while preserving the nutritional and health qualities of the product.

Abstract Background ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

Gastroenteropancreatic neuroendocrine tumors (NETs), also historically known as carcinoids, are tumors derived of hormone-secreting enteroendocrine cells. Carcinoids may be found in the esophagus, stomach, small intestine, appendix, colon, rectum, or pancreas. The biologic behavior of carcinoids differs based on their location, with gastric and appendiceal NETs among the least aggressive and small intestinal and pancreatic NETs among the most aggressive. Ultimately, however, biologic behavior is most heavily influenced by tumor grade. The incidence of NETs has increased by 6.4 times over the past 40 years. Surgery remains the mainstay for management of most carcinoids. Medical management, however, is a useful adjunct and/or definitive therapy in patients with symptomatic functional carcinoids, in patients with unresectable or incompletely resected carcinoids, in some cases of recurrent carcinoid, and in postoperative patients to prevent recurrence. Functional tumors with persistent symptoms or progressive metastatic carcinoids despite therapy are called "resistant" tumors. In patients with unresectable disease and/or carcinoid syndrome, an array of medical therapies is available, mainly including somatostatin analogues, molecular-targeted therapy, and peptide receptor radionuclide therapy. Active research is ongoing to identify additional targeted therapies for patients with resistant carcinoids. [ABSTRACT FROM AUTHOR]

Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.

Improving soil-water relations by amending soil with biochar might play a significant role in increasing water availability for agricultural crops as well as decreasing water loss through drainage or runoff. While the effects of biochar on the hydrological properties on coarse-textured soils are generally positive and well-documented in the literature, studies on biochar effects on fine-textured soils are rather scarce and even contradictory. Therefore, the aim of this paper was to investigate the impact of biochar on the bulk density, water retention curve (together with several water capacitive indicators) and water infiltration rate in a clay loam soil. A pot experiment was carried out under lab conditions in which biochar was mixed with soil at rates of 0 (B0 or control), 2, 4, 6, 8 and 10% dw (B2, B4, B6, B8 and B10, respectively). Water retention of soil–biochar mixtures at different matrix potentials was determined using a pressure plate apparatus. From these measurements, a series of capacitive indicators was derived and the fitting of the van Genuchten model was also performed. Water infiltration into soil–biochar mixtures was measured by means of a mini-disk infiltrometer and the obtained data were analyzed both directly and by fitting the Philip’s model. Biochar significantly affected the considered soil properties. As the biochar rate increased, the bulk density decreased and water retention increased (B6, B8 and B10 > B2, B4 and B0), while the infiltration rate decreased (B0 > B2, B4, B6, B8 and B10). Although the experiment was performed on sieved and repacked soil samples under lab conditions, the results confirmed that biochar has the potential to increase plant-available water, while possibly reducing drainage water in a clay loam soil by lowering the infiltration rate.

In recent years, soil addition with organic amendments, such as biochar and compost, has gained attention as an effective agronomic practice to sustain soil fertility, enhance plant growth and crop yield. Well known are the positive effects of compost on yield of a wide crop varieties, while both positive and negative responses are reported for biochar Therefore, the aim of the study was to verify the effect of biochar mixed with three types of compost on quanti-qualitative response of Swiss chard (Beta vulgaris L. cycla), a leafy green vegetable rich in dietary antioxidants, largely consumed worldwide. A factorial experiment in pots with two factors, including biochar (without biochar and with biochar from vine pruning residues) and compost (without compost, with compost from olive pomace, with vermicompost from cattle manure, and with compost from cattle anaerobic digestate), was setup. Two growth cycles were considered, and a set of quantitative (height of plants, number, area and fresh weight of leaves) and qualitative parameters (carotenoids, chlorophyll, total N, and NO3−content of leaves) were analyzed. Biochar decreased plant growth and NO3− leaf content; on the contrary, it increased total N leaf content, while compost improved all the considered parameters. The interactive effect of biochar and compost was evident only on total N and NO3− leaf content. In our experimental conditions, the compost showed to be the best option to improve Swiss chard growth and increase the content of phytopigments, while the biochar-compost mixtures did not produce the expected effect.

In the EU, bioenergy is by far the most significant renewable energy source and more than two thirds of biomass utilized for energy conversion consists of forestry and agricultural residues, such as fruit tree pruning. Although still underutilized, biomass from pruning is a relevant energy feedstock that does not generate additional demand for land, nor negative impact on the environment and biodiversity. On the other hand, previously shredded pruning left in the field may sustain agricultural processes and help provide beneficial ecological services. In the latter case, the most relevant result is the increase in soil organic carbon, an essential factor for improving soil quality and promoting climate regulation. As a result, a “dilemma” arises for farmers over two conflicting pruning management options: “pruning to energy” vs. “pruning to soil”, respectively. The present study, performed in the frame of the Horizon 2020 project “uP_running”, is offering a straightforward evaluation tool to assess weather biomass resulting from fruit tree pruning could be removed from the field and used as energy feedstock without compromising both soil quality and the provision of important ecosystem services.

Soil addition with organic amendments is an issue that receives growing attention in the agricultural sector. However, the effects of such materials on plant growth and crop yield are highly variable in the literature. This study aims to evaluate the influence of soil addition with biochar (from vine pruning residues), vermicompost (from cattle manure), and three different composts (from olive pomace or cattle anaerobic digestate), on the quali-quantitative response of Swiss chard (Beta vulgaris L. var. cycla) grown in pots. The organic amendments were applied to the soil in two doses to provide 140 and 280 kg N ha−1, respectively. Two growth cycles were considered, and, at each leaf cut, plants were analyzed for growth parameters (height, fresh weight, leaf number, and leaf area) and qualitative characteristics (nitrogen, nitrate, and pigment leaf content). Swiss chard responded positively to organic amendment and, particularly when the soil was treated with compost from animal wastes, higher plant growth and pigment leaf content were observed. Nitrate leaf content was always well below the NO3− thresholds established by the European Commission Regulations. Biochar application did not show a positive effect on the quali-quantitative characteristics of Swiss chard, likely due to benefits that may be achieved over time.

European lacustrine systems are frequently exposed to nitrate (NO3–) pollution causing eutrophication processes. An example of these lakes is Shkodra Lake, a large, shallow lake shared by Albania and Montenegro, in the Balkans Peninsula. Shkodra Lake is a natural sink that collects NO3– from agricultural activities, widely diffused in the surrounding area. The additions of wheat straw and biochar have been suggested to increase soil NO3– retention of agricultural lands. To better understand the role of these two organic soil amendments in mitigating NO3– leaching from arable lands, a pot experiment using a representative sandy loam soil of the Skodra Lake basin was performed. More specifically, a greenhouse experiment with Lolium multiflorum L. and Zea mays L., was carried out for three months, to evaluate the concentrations of NO3–-N in leachate and the cumulative leaching losses of NO3–-N, after wheat straw (10 Mg ha–1) and biochar (10 Mg ha–1) soil addition, under the same rate of NPK fertiliser (300 kg ha–1). The effect of the two organic amendments on nitrate retention, was evaluated according to two methods: i) Soil NO3–-N leaching with distilled water; and ii) Soil NO3–-N extraction with 2M KCl. The leached NO3–-N and the Potentially Leachable NO3–-N (2M KCl extraction) were respectively determined. N uptake by plants, as well as the Nitrogen Use Efficiency were also calculated. A retention effect on nitrate was found in Lolium multiflorum L. and wheat straw treatments compared to control, by reducing leached NO3–-N almost to 35%. In SBFL (soil+biochar+fertiliser+Lolium) treatment, biochar effectively reduced the total amount of nitrate in leachate of 27% and 26% compared to SFL (soil+fertiliser+Lolium) and SSFL (soil+straw+fertiliser+Lolium) treatments, respectively. The potentially leachable NO3–-N was two to four times higher than the leached NO3–-N. The amount of potentially leachable NO3–-N per hectare ranged from 220 in SL (soil+Lolium) treatment, to 500 kg ha–1 in SFL. N plant uptake values ranged from 18.16 mg kg–1 in the non- fertilised treatment to 58.06 mg kg–1 soil in SSFM (soil+straw+fertiliser+maize) treatment. The NUE showed a similar trend (from 0 in the non-fertilised treatment to 47.9 % in SSFM). Results indicated a mitigating action of biochar on leaching of NO3–-N (leached up to 100 kg ha–1), despite the retention effect of the two different amendments applied.

The goal of this study was to develop a method for whole genome cell-free DNA (cfDNA) methylation analysis in humans and mice with the ultimate goal to facilitate the identification of tumor derived DNA methylation changes in the blood. Plasma or serum from patients with pancreatic neuroendocrine tumors or lung cancer, and plasma from a murine model of pancreatic adenocarcinoma was used to develop a protocol for cfDNA isolation, library preparation and whole-genome bisulfite sequencing of ultra low quantities of cfDNA, including tumor-specific DNA. The protocol developed produced high quality libraries consistently generating a conversion rate >98% that will be applicable for the analysis of human and mouse plasma or serum to detect tumor-derived changes in DNA methylation.

At the same time with population In many arid and semi-arid countries water is becoming an increasingly scarce resource and so it is fundamental to consider any sources of water including treated agro-industrial wastewater which might be used economically and effectively to promote further development. This study was carried out at Fiordelisi company (Stornarella; 41° 15’N, 15° 44’E; altitude, 154 m a.s.l.), which produces processing vegetables (i.e., tomato, broccoli, eggplant, zucchini, pepper) and is equipped with a wastewater treatment plant based on the following steps: screening, oil removal, equalization, activated sludge process (anoxic plus aerobic phases), chemically assisted sedimentation, sand filtration (preceded by chlorination), membrane ultrafiltration (Kristal 600ER -Hyflux - nominal pore size of 0.05 µm), UV disinfection (6 mercury- vapor lamps, 300W each). During the study three types of water (groundwater - GW -; secondary treated agro-industrial wastewater -SW - and tertiary treated agro-industrial wastewater -TW -) were used for irrigation of processing tomato and broccoli crops, to evaluate the main effects on plant nutrient contents of the soil. The experimental trials were carried out in open field over three growing seasons of the considered crops, from April 2012 to February 2015. Compared to GW, SW and TW were characterized by higher contents of plant nutrient, such as NH4-N,NO2-N, PO42-, K+, Ca2+, Mg2+, TSS and organic matter. On the contrary, GW showed higher NO3-N content. However, considering the seasonal irrigation volumes applied to tomato and broccoli crops, a significantly nutrients load in the soil was observed only for K+ and NO3-N.