The Best of Times, the Worst of Times: Understanding Pro-cyclical Mortality

A growing literature documents cyclical movements in mortality and health. We examine this pattern more closely and attempt to identify the mechanisms behind it. Specifically, we distinguish between mechanisms that rely on fluctuations in own employment or time use and those involving factors that are external to the individual. Our investigation suggests that changes in individuals’ own behavior contribute very little to pro-cyclical mortality. Looking across broad age and gender groups, we find that own-group employment rates are not systematically related to own-group mortality. In addition, we find that most of the additional deaths that occur during times of economic growth are among the elderly, particularly elderly women, who have limited labor force attachment. Focusing on mortality among the elderly, we show that cyclicality is especially strong for deaths occurring in nursing homes, and is stronger in states where a higher fraction of the elderly reside in nursing homes. We also demonstrate that staffing in skilled nursing facilities moves counter-cyclically. Taken together, these findings suggest that cyclical fluctuations in the mortality rate may be largely driven by fluctuations in the quality of health care.

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

The relevance of gemcitabine timing for chronotherapeutic optimisation was investigated. Healthy mice received multiple doses of gemcitabine (120, 160 or 200 mg kg−1 injection (inj)−1) at one of six circadian times (3, 7, 11, 15, 19 or 23 h after light onset – HALO) on days 1, 4, 7 and 10 or a single dose of gemcitabine (400 mg kg−1) at 11 or 23 HALO±cisplatin (5 mg kg−1 at 1 min, 4 or 8 h later). Mice bearing Glasgow osteosarcoma received multiple doses of gemcitabine (200 mg kg−1 inj−1) at 11 or 23 HALO±cisplatin (5 mg kg−1 inj−1 at 1 min or 4 h later) on days of 10, 13, 16 and 19 following tumour inoculation. A circadian rhythm in body weight loss was statistically validated, with 1030 HALO corresponding to the least toxic time (95% CL, 0800 to 1300). Gemcitabine dosing produced least body weight loss and least neutropenia after injection at 11 vs 23 HALO, whether the drug was given alone or with cisplatin (P=0.001). Gemcitabine–cisplatin tolerability was improved by dosing gemcitabine at 11 HALO and CDDP at 15 HALO (P<0.001). The administration of this schedule to tumour-bearing mice increased median survival three-fold as compared to treatments where both drugs were given simultaneously at 11 or 23 HALO (P=0.02). The optimal schedule would correspond to the delivery of gemcitabine upon awakening and cisplatin near mid-activity in cancer patients

Large scale variation in the rate of germ-line de novo mutation, base composition, divergence and diversity in humans

It has long been suspected that the rate of mutation varies across the human genome at a large scale based on the divergence between humans and other species. However, it is now possible to directly investigate this question using the large number of de novo mutations (DNMs) that have been discovered in humans through the sequencing of trios. We investi- gate a number of questions pertaining to the distribution of mutations using more than 130,000 DNMs from three large datasets. We demonstrate that the amount and pattern of variation differs between datasets at the 1MB and 100KB scales probably as a consequence of differences in sequencing technology and processing. In particular, datasets show differ- ent patterns of correlation to genomic variables such as replication time. Never-the-less there are many commonalities between datasets, which likely represent true patterns. We show that there is variation in the mutation rate at the 100KB, 1MB and 10MB scale that can- not be explained by variation at smaller scales, however the level of this variation is modest at large scales–at the 1MB scale we infer that ~90% of regions have a mutation rate within 50% of the mean. Different types of mutation show similar levels of variation and appear to vary in concert which suggests the pattern of mutation is relatively constant across the genome. We demonstrate that variation in the mutation rate does not generate large-scale variation in GC-content, and hence that mutation bias does not maintain the isochore struc- ture of the human genome. We find that genomic features explain less than 40% of the explainable variance in the rate of DNM. As expected the rate of divergence between spe- cies is correlated to the rate of DNM. However, the correlations are weaker than expected if all the variation in divergence was due to variation in the mutation rate. We provide evidence that this is due the effect of biased gene conversion on the probability that a mutation will become fixed. In contrast to divergence, we find that most of the variation in diversity can be explained by variation in the mutation rate. Finally, we show that the correlation between divergence and DNM density declines as increasingly divergent species are considered

Circadian optimisation of irinotecan and oxaliplatin efficacy in mice with Glasgow osteosarcoma

The relevance of circadian rhythms in irinotecan and oxaliplatin tolerability was investigated with regard to antitumour activity. Mice bearing Glasgow osteosarcoma (GOS) received single agent irinotecan (50 or 60 mg kg−1 per day) or oxaliplatin (4 or 5.25 mg kg−1 per day) at one of six dosing times expressed in hours after light onset (3, 7, 11, 15, 19 or 23 hours after light onset). Irinotecan (50 mg kg−1 per day) and oxaliplatin (4 or 5.25 mg kg−1 per day) were given 1 min apart at 7 or 15 hours after light onset, or at their respective times of best tolerability (7 hours after light onset for irinotecan and 15 hours after light onset for oxaliplatin) or worst tolerability (15 hours after light onset for irinotecan and 7 hours after light onset for oxaliplatin). Tumour growth rate was nearly halved and per cent increase in estimated life span (% ILS) was – doubled in the mice receiving irinotecan at 7 hours after light onset as compared to 15 hours after light onset (P<0.05). Results of similar magnitude were obtained with oxaliplatin for both endpoints, yet with 7 hours after light onset corresponding to least efficacy and 15 hours after light onset to best efficacy (P<0.05). Irinotecan addition to oxaliplatin proved therapeutic benefit only if the schedule consisted of irinotecan administration at 7 hours after light onset and oxaliplatin delivery at 15 hours after light onset, i.e. when both drugs were given near their respective ‘best’ circadian times. These would correspond to the middle of the night for irinotecan and the middle of the day for oxaliplatin in humans

Key international comparison of AC-DC current transfer standards CCEM-K12

The circulation of the travelling standards in the CIPM key comparison CCEM-K12 of AC–DC current transfer difference began in March 2005 and was completed in April 2007. The travelling standards were lost on their way from the last participant to the pilot laboratory. Since, prior to their disappearance, the travelling standards exhibited exceptional stability, the CCEM Working Group on Low-Frequency Quantities decided in June 2008 to accept the results of the comparison as valid without the final measurement by the pilot laboratory. The AC–DC transfer differences of the travelling standards have been measured at 10 mA and 5 A, and at the frequencies 10 Hz, 55 Hz, 1 kHz, 10 kHz, 20 kHz, 50 kHz and 100 kHz. The key comparison reference values were calculated as the weighted means of the results of the National Metrology Institutes (NMIs) with independent realizations of primary standards and low reported uncertainties. The degrees of equivalence relative to the key comparison reference values, as well as between pairs of NMIs, have been determined for the measurement points and show very good agreement. All but three of the calculated degrees of equivalence relative to the key comparison reference values are within the limits of the expanded uncertainties.Fil: Budovsky, Ilya. National Measurement Institute (NMIA); AustraliaFil: Lipe, Thomas E. National Institute of Standards and Technology (NIST); Estados UnidosFil: Filipski, Peter S. National Research Council Canada. Institute for National Measurement Standards (NRC-INMS); CanadáFil: Laiz, Hector. Instituto Nacional de Tecnología Industrial (INTI); ArgentinaFil: Funck, Torsten. Physikalisch-Technische Bundesanstalt (PTB); AlemaniaFil: Garcocz, Martin. Bundesamt für Eich- und Vermessungswesen (BEV); AustriaFil: Espedalen, Jeanne H. Justervesenet (JV); NoruegaFil: Rydler, Karl-Erik. SP Technical Research Institute of Sweden; SueciaFil: Chua. Sze Wey. National Metrology Centre (NMC); SingapurFil: Borghi, Giovanna. Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMetro); BrasilFil: Wheaton, Adrian. National Physical Laboratory (NPL); Reino UnidoFil: Telitchenko, G. P. D. I. Mendeleev Institute for Metrology (VNIIM); Rusi

Immunotherapy Approaches for the Treatment of Diffuse Midline Gliomas

Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients

Tumor Growth Rate Determines the Timing of Optimal Chronomodulated Treatment Schedules

In host and cancer tissues, drug metabolism and susceptibility to drugs vary in a circadian (24 h) manner. In particular, the efficacy of a cell cycle specific (CCS) cytotoxic agent is affected by the daily modulation of cell cycle activity in the target tissues. Anti-cancer chronotherapy, in which treatments are administered at a particular time each day, aims at exploiting these biological rhythms to reduce toxicity and improve efficacy of the treatment. The circadian status, which is the timing of physiological and behavioral activity relative to daily environmental cues, largely determines the best timing of treatments. However, the influence of variations in tumor kinetics has not been considered in determining appropriate treatment schedules. We used a simple model for cell populations under chronomodulated treatment to identify which biological parameters are important for the successful design of a chronotherapy strategy. We show that the duration of the phase of the cell cycle targeted by the treatment and the cell proliferation rate are crucial in determining the best times to administer CCS drugs. Thus, optimal treatment times depend not only on the circadian status of the patient but also on the cell cycle kinetics of the tumor. Then, we developed a theoretical analysis of treatment outcome (TATO) to relate the circadian status and cell cycle kinetic parameters to the treatment outcomes. We show that the best and the worst CCS drug administration schedules are those with 24 h intervals, implying that 24 h chronomodulated treatments can be ineffective or even harmful if administered at wrong circadian times. We show that for certain tumors, administration times at intervals different from 24 h may reduce these risks without compromising overall efficacy

Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis

PURPOSE: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy. METHODS: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected. RESULTS: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI. CONCLUSION: A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-022-04049-w

A guideline for analyzing circadian wheel-running behavior in rodents under different lighting conditions

Most behavioral experiments within circadian research are based on the analysis of locomotor activity. This paper introduces scientists to chronobiology by explaining the basic terminology used within the field. Furthermore, it aims to assist in designing, carrying out, and evaluating wheel-running experiments with rodents, particularly mice. Since light is an easily applicable stimulus that provokes strong effects on clock phase, the paper focuses on the application of different lighting conditions