Higher biomass accumulation by increasing phosphoribosylpyrophosphate synthetase activity in Arabidopsis thaliana and Nicotiana tabacum

Plants are able to produce all the organic compounds required for development and growth. As developmental processes and metabolic pathways use a common resource pool, the tight regulation of the distribution of metabolites between growth, production of defence compounds and storage products can be assumed. A transgenic approach was used to investigate the importance of supplying the key intermediate phosphoribosylpyrophosphate (PRPP) for plant growth and biomass accumulation in the model plant Arabidopsis thaliana and in Nicotiana tabacum. For this purpose, the Ashbya gossypii genes coding for either PRPP synthetase (PRS) or a mutated variant of the same gene were over-expressed under the control of a constitutive promoter. It was shown that increased PRS activity in A. thaliana or N. tabacum leads to a substantial increase in biomass accumulation under different standardized growth conditions. Growth enhancement was accompanied by significant changes in the amount of sugars and other metabolites. This study provides evidence that the supply of PRPP co-limits growth rates, and has obvious implications for biotechnological strategies aiming to increase plant biomass as an alternative renewable energy source

Urgent Considerations for the Neuro-oncologic Treatment of Patients with Gliomas During the COVID-19 Pandemic.

The COVID-19 outbreak is posing unprecedented risks and challenges for all communities and healthcare systems, worldwide. There are unique considerations for many adult patients with gliomas who are vulnerable to the novel coronavirus due to older age and immunosuppression. As patients with terminal illnesses, they present ethical challenges for centers that may need to ration access to ventilator care due to insufficient critical care capacity. It is urgent for the neuro-oncology community to develop a pro-active and coordinated approach to the care of adults with gliomas in order to provide them with the best possible oncologic care while also reducing their risk of viral infection during times of potential healthcare system failure. In this article, we present an approach developed by an international multi-disciplinary group to optimize the care of adults with gliomas during this pandemic. We recommend measures to promote strict social distancing and minimize exposures for patients, address risk and benefit of all therapeutic interventions, pro-actively develop end of life plans, educate patients and caregivers and ensure the health of the multi-disciplinary neuro-oncology workforce. This pandemic is already changing neuro-oncologic care delivery around the globe. It is important to highlight opportunities to maximize the benefit and minimize the risk of glioma management during this pandemic and potentially, in the future

European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme

BACKGROUND: Glufosfamide is a new alkylating agent in which the active metabolite of isophosphoramide mustard is covalently linked to beta-D-glucose to target the glucose transporter system and increase intracellular uptake in tumor cells. We investigated this drug in a multicenter prospective phase II trial in recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent GBM following surgery, radiotherapy and no more than one prior line of chemotherapy. Patients were treated with glufosfamide 5000 mg/m(2) administered as a 1-h intravenous infusion. Treatment success was defined as patients with either an objective response according to Macdonald's criteria or 6 months progression-free survival. Toxicity was assessed with the Common Toxicity Criteria (CTC) version 2.0. RESULTS: Thirty-one eligible patients were included. Toxicity was modest, the main clinically relevant toxicities being leukopenia (CTC grade >3 in five patients) and hepatotoxicity (in three patients). No responses were observed; one patient (3%; 95% confidence interval 0 to 17%) was free from progression at 6 months. Pharmacokinetic analysis showed a 15% decrease in area under the curve and glufosfamide clearance in patients treated with enzyme-inducing antiepileptic drugs, but no effect of these drugs on maximum concentration and plasma half-life. CONCLUSION: Glufosfamide did not show significant clinical antitumor activity in patients with recurrent GBM

Memory in low-grade glioma patients treated with radiotherapy or temozolomide: a correlative analysis of EORTC study 22033-26033.

EORTC study 22033-26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment. Considering the potential long-term deleterious impact of RT on memory functioning, this study aims to determine whether TMZ is associated with less impaired memory functioning. Using the Visual Verbal Learning Test (VVLT), memory functioning was evaluated at baseline and subsequently every 6 months. Minimal compliance for statistical analyses was set at 60%. Conventional indices of memory performance (VVLT Immediate Recall, Total Recall, Learning Capacity, and Delayed Recall) were used as outcome measures. Using a mixed linear model, memory functioning was compared between treatment arms and over time. Neuropsychological assessment was performed in 98 patients (53 RT, 46 TMZ). At 12 months, compliance had dropped to 66%, restricting analyses to baseline, 6 months, and 12 months. At baseline, patients in either treatment arm did not differ in memory functioning, sex, age, or educational level. Over time, patients in both arms showed improvement in Immediate Recall (P = 0.017) and total number of words recalled (Total Recall; P < 0.001, albeit with delayed improvement in RT patients (group by time; P = 0.011). Memory functioning was not associated with RT gross, clinical, or planned target volumes. In patients with high-risk low-grade glioma there is no indication that in the first year after treatment, RT has a deleterious effect on memory function compared with TMZ chemotherapy

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Impact of timing of antiseizure medication withdrawal on seizure recurrence in glioma patients:a retrospective observational study

Background: Withdrawal of antiseizure medication treatment (ASM) can be considered after completion of antitumour treatment in glioma patients who no longer suffer from seizures. We compared the risk for recurrent seizures after ASM withdrawal between patients with short-term, medium-term versus long-term seizure freedom after antitumour treatment. Methods: In this retrospective observational study, the primary outcome was time to recurrent seizure, from the starting date of no ASM treatment up to 36 months follow-up. Cox proportional hazards models were used to study the effect of risk factors on time to recurrent seizure. Stratification was done with information known at baseline. Short-term seizure freedom was defined as ≥ 3 months, but &lt; 12 months; medium-term as 12–24 months; and long-term as ≥ 24 months seizure freedom from the date of last antitumour treatment. Results: This study comprised of 109 patients; 31% (34/109) were in the short-term, 29% (32/109) in the medium-term, and 39% (43/109) in the long-term group. A recurrent seizure was experienced by 47% (16/34) of the patients in the short-term, 31% (10/32) in the medium-term, and 44% (19/43) in the long-term group. Seizure recurrence risk was similar between patients in the short-term group as compared to the medium-term (cause-specific adjusted hazard ratio [aHR] = 0.65 [95%CI = 0.29–1.46]) and long-term group (cause-specific aHR = 1.04 [95%CI = 0.52–2.09]). Conclusions: Seizure recurrence risk is relatively similar between patients with short-term, medium-term, and long-term seizure freedom after completion of antitumour treatment.</p