Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Interactions between canopy structure and herbaceous biomass along environmental gradients in moist forest and dry miombo woodland of Tanzania

We have limited understanding of how tropical canopy foliage varies along environmental gradients, and how this may in turn affect forest processes and functions. Here, we analyse the relationships between canopy leaf area index (LAI) and above ground herbaceous biomass (AGBH) along environmental gradients in a moist forest and miombo woodland in Tanzania. We recorded canopy structure and herbaceous biomass in 100 permanent vegetation plots (20 m × 40 m), stratified by elevation. We quantified tree species richness, evenness, Shannon diversity and predominant height as measures of structural variability, and disturbance (tree stumps), soil nutrients and elevation as indicators of environmental variability. Moist forest and miombo woodland differed substantially with respect to nearly all variables tested. Both structural and environmental variables were found to affect LAI and AGBH, the latter being additionally dependent on LAI in moist forest but not in miombo, where other factors are limiting. Combining structural and environmental predictors yielded the most powerful models. In moist forest, they explained 76% and 25% of deviance in LAI and AGBH, respectively. In miombo woodland, they explained 82% and 45% of deviance in LAI and AGBH. In moist forest, LAI increased non-linearly with predominant height and linearly with tree richness, and decreased with soil nitrogen except under high disturbance. Miombo woodland LAI increased linearly with stem density, soil phosphorous and nitrogen, and decreased linearly with tree species evenness. AGBH in moist forest decreased with LAI at lower elevations whilst increasing slightly at higher elevations. AGBH in miombo woodland increased linearly with soil nitrogen and soil pH. Overall, moist forest plots had denser canopies and lower AGBH compared with miombo plots. Further field studies are encouraged, to disentangle the direct influence of LAI on AGBH from complex interrelationships between stand structure, environmental gradients and disturbance in African forests and woodlands

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Nanoscale mechanical properties of single biomolecules by AFM

In the past 25 years the atomic force microscope (AFM) has become a true enabling platform in the life sciences opening entire novel avenues for structural and dynamic studies of biological systems. It enables visualization, probing and manipulation across the length scales, from single molecules to living cells in buffer solution under physiological conditions without the need for labeling or staining of the pecimen. Currently there is a great interest in AFM based high resolution echanical mapping techniques providing single molecule resolution of mechanical properties to derive molecular structure-function relationships. In this article selected examples of the recent literature are highlighted including own results obtained by peak force tapping AFM to elaborate the mechanical properties of lysozyme molecules adsorbed to mica substrates

Pulmonary function in infants with swallowing dysfunction.

Swallowing dysfunction can lead to recurring aspiration and is frequently associated with chronic symptoms such as cough and wheezing in infants. Our objective was to describe the characteristics of infants with swallowing dysfunction, determine if pulmonary function abnormalities are detectable, and if they improve after therapy.We studied 38 infants with a history of coughing and wheezing who had pulmonary function tests performed within two weeks of their diagnosis of swallowing dysfunction. The raised lung volume rapid thoracoabdominal compression technique was used. After 6 months of therapy, 17 of the infants repeated the tests.Initially, 25 had abnormal spirometry, 18 had abnormal plethysmography, and 15 demonstrated bronchodilator responsiveness. Six months later test were repeated for seventeen patients. Ten patients had continued abnormal spirometry, two patients remained normal, three patients' abnormal spirometry had normalized, and two patients' previously normal studies became abnormal. Eight of the 17 patients had continued abnormal plethysmography, six had continued normal plethysmography, and three patients' normal plethysmography became abnormal. After 6 months of treatment, eight patients demonstrated bronchodilator responsiveness, of which five continued to demonstrate bronchodilator responsiveness and three developed responsiveness. The remainder either continued to be non- bronchodilator responsive (two) or lost responsiveness (three.) The findings of the abnormal tests in most infants tested is complicated by frequent occurrence of other co-morbidities in this population, including gastroesophageal reflux in 23 and passive smoke exposure in 13 of the infants.The interpretation of lung function changes is complicated by the frequent association of swallowing dysfunction with gastroesophageal reflux and passive smoke exposure in this population. Six months of medical therapy for swallowing dysfunction/gastroesophageal reflux did not significantly improve pulmonary function in these infants. Long-term studies will be necessary to determine which of these changes persists into adulthood

Demographics of patients who had both first and second pulmonary function tests.

<p>M, male; F, female; AA, African American; C, Caucasian; Y, yes; N, no; NE, not evaluated; PA, penetration-aspiration, PBT, peribronchial thickening.</p><p>Demographics of patients who had both first and second pulmonary function tests.</p