Dose mimicking based strategies for online adaptive proton therapy of head and neck cancer.

Objective.To compare a not adapted (NA) robust planning strategy with three fully automated online adaptive proton therapy (OAPT) workflows based on the same optimization method: dose mimicking (DM). The added clinical value and limitations of the OAPT methods are investigated for head and neck cancer (HNC) patients.Approach.The three OAPT strategies aimed at compensating for inter-fractional anatomical changes by mimiking different dose distributions on corrected cone beam CT images (corrCBCTs). Order by complexity, the OAPTs were: (1) online adaptive dose restoration (OADR) where the approved clinical dose on the planning-CT (pCT) was mimicked, (2) online adaptation using DM of the deformed clinical dose from the pCT to corrCBCTs (OADEF), and (3) online adaptation applying DM to a predicted dose on corrCBCTs (OAML). Adaptation was only applied in fractions where the target coverage criteria were not met (D98% < 95% of the prescribed dose). For 10 HNC patients, the accumulated dose distributions over the 35 fractions were calculated for NA, OADR, OADEF, and OAML.Main results.Higher target coverage was observed for all OAPT strategies compared to no adaptation. OADEF and OAML outperformed both NA and OADR and were comparable in terms of target coverage to initial clinical plans. However, only OAML provided comparable NTCP values to those from the clinical dose without statistically significant differences. When the NA initial plan was evaluated on corrCBCTs, 51% of fractions needed adaptation. The adaptation rate decreased significantly to 25% when the last adapted plan with OADR was selected for delivery, to 16% with OADEF, and to 21% with OAML. The reduction was even greater when the best plan among previously generated adapted plans (instead of the last one) was selected.Significance. The implemented OAPT strategies provided superior target coverage compared to no adaptation, higher OAR sparing, and fewer required adaptations.

Radiation therapy-induced left vocal cord paralysis following lung stereotactic body radiation therapy: A case report and review of the literature.

We report the case of a 50-year old women with an oncological history of metastatic breast carcinoma who underwent lung stereotactic body radiation therapy (SBRT) of 60Gy in 8 fractions for a left upper lobe metastatic lesion. Seven months later, she complains about hoarseness and weakness of voice. Tumoral relapse and other frequent etiologies were excluded. The diagnosis of radiation induced left recurrent laryngeal nerve paralysis causing left vocal cord paralysis (VCP) was made. The symptomatology did not improve till the disease progression and death of the patient 29 months after SBRT. VCP after lung SBRT is a rare adverse event that has not yet been well described in the medical literature.

Impact of the gut microbiome on immune checkpoint inhibitor efficacy-a systematic review.

Background: Immune checkpoint inhibitors (icis) are increasingly being used in clinical practice, improving outcomes for cancer patients. Preclinical models showed significant interaction between the gut microbiome (gm) and response to icis. However, that interaction remains unclear in clinical practice. Methods: We performed a systematic review in medline to determine■ whether antibiotics affect ici efficacy,■ whether baseline gm composition and ici efficacy show any correlations,■ whether baseline gm composition and emergence of immune-related adverse events (iraes) show any correlations, and■ whether gm manipulation can alleviate the iraes.Included publications had to be written in English or French and had to describe a quantifiable link between gm composition or its modification and the response to icis or the occurrence of iraes, or both. Results: Of 1451 articles published before December 2018, 13 publications met the inclusion criteria. Five full-text articles and two abstracts highlighted a negative effect of antibiotics on ici efficacy. The composition of the gm was associated with ici efficacy in five full-text articles and one abstract, and with iraes in two full-text articles. In 2 cases, fecal microbiota transplantation was reported to reduce immune colitis. Conclusions: If possible, antibiotics should be avoided before ici treatment because of their negative effect on ici anticancer efficacy. No specific commensal bacterium was associated with ici efficacy, but an intact gm with high bacterial diversity and a good ratio of "responder-associated" bacteria to "non-responder-associated" bacteria seem to be correlated with better patient outcomes. Fecal microbiota transplantation is a promising technique for reducing ici-associated colitis.

Mechanism of action of K channel openers on skeletal muscle KATP channels. Interactions with nucleotides and protons.

The molecular mechanisms underlying the actions of K channel openers (KCOs) on KATP channels were studied with the patch clamp technique in excised inside-out patches from frog skeletal muscle fibers. Benzopyran KCOs (levcromakalim and SR 47063) opened channels partially blocked by ATP, ADP, or ATP gamma s, with and without Mg2+, but they had no effects in the absence of internal nucleotides, even after channel activity had significantly declined because of rundown. The effects of KCOs could therefore be attributed solely to a competitive interaction between KCOs and nucleotides, as confirmed by observations that ATP decreased the apparent affinity for KCOs and that, conversely, KCOs decreased ATP or ADP sensitivity. Protons antagonized the action of the non-benzopyran KCOs, pinacidil and aprikalim, by enhancing their dissociation rate. This effect resembled the effect of acidification on benzopyran KCOs (Forestier, C., Y. Depresle, and M. Vivaudou. FEBS Lett. 325:276-280, 1993), suggesting that, in spite of their structural diversity, KCOs could act through the same binding sites. Detailed analysis of the inhibitory effects of protons on channel activity induced by levcromakalim or SR 47063 revealed that, in the presence of 100 microM ATP, this effect developed steeply between pH 7 and 6 and was half maximal at pH 6.6. These results are in quantitative agreement with an allosteric model of the KATP channel possessing four protonation sites, two nucleotidic sites accessible preferentially to Mg(2+)-free nucleotides, and one benzopyran KCO site. The structural implications of this model are discussed.

Sequence and transcript analysis of the nitrogenase structural gene operon (nifHDK) of Rhodobacter capsulatus: evidence for intramolecular processing of nifHDK mRNA.

Northern blot analysis of RNA prepared from cells of Rhodobacter capsulatus derepressed for nitrogenase (N2ase) synthesis, using a 6.0-kb DNA probe containing the entire nifHDK operon, revealed the presence of at least six hybridizing species of the estimated sizes, 4.4, 3.5, 2.7, 1.3, 0.9 and 0.38 kb. No hybridization was detected with RNA prepared from cells grown in the presence of an excess of NH4+, which represses N2ase synthesis. Hybridization with gene-specific probes revealed that the 4.4-kb species hybridized with all three probes, and presumably corresponded to the full-length nifHDK transcript, whereas the 3.5-kb species hybridized with nifD and nifK only, and the 2.7-kb transcript hybridized with nifH and nifD. The 1.3 and 0.9-kb species hybridized with all three probes, but appeared to hybridize most strongly with nifH. In contrast, the 0.38-kb species hybridized with none of the gene-specific probes, and was also detected in RNA from cells of strain RcM1, which contains a chromosomal deletion of the nifHDK operon. This species probably corresponds to the transcript of a gene, named fdxD, which was found to be located just upstream from the nifHDK operon. Nucleotide (nt) sequencing of the nifH-D and nifD-K intergenic regions revealed the presence of inverted repeat (IR) sequences potentially capable of forming stable stem-loop structures in mRNA. Primer extension analysis of the nifDK-homologous species showed that the 5' end was located one or two nt downstream from the IR sequence between nifH and nifD, suggesting that the putative stem-loop structure may be a target for intramolecular processing of the nifHDK mRNA.

Site-directed mutagenesis of the target arginine for ADP-ribosylation of nitrogenase component II in Rhodobacter capsulatus.

The role of the conserved residue arginine-102 in the functioning and the regulation of the nitrogenase component II protein in Rhodobacter capsulatus has been studied by site-directed mutagenesis. The arginine at position 102 was replaced by thirteen different amino acids, and the effect of these substitutions on diazotrophic growth, in vivo and in vitro nitrogenase activity, and ADP-ribosylation of the component II protein was tested. The results show that although arginine is the optimal amino acid at this position, it is not essential for activity. However, the mutant proteins were not modified by ADP-ribosylation, either in the dark or after addition of NH4+, consistent with the specificity of the post-translational regulatory mechanism for the Arg-102. Indirect evidence suggest that this residue may be involved in interaction with the in vivo low-potential electron donor.

Posttranslational regulation of nitrogenase in Rhodobacter capsulatus: existence of two independent regulatory effects of ammonium.

In the photosynthetic bacterium Rhodobacter capsulatus, nitrogenase activity is regulated by ADP-ribosylation of component II in response to the addition of ammonium to cultures or to the removal of light. The ammonium stimulus results in a fast and almost complete inhibition of the in vivo acetylene reduction activity, termed switch-off, which is reversed after the ammonium is exhausted. In the present study of the response of cells to ammonium, ADP-ribosylation of component II occurred but could not account for the extent and timing of the inhibition of activity. The presence of an additional response was confirmed with strains expressing mutant component II proteins; although these proteins are not a substrate for ADP-ribosylation, the strains continued to exhibit a switch-off response to ammonium. This second regulatory response of nitrogenase to ammonium was found to be synchronous with ADP-ribosylation and was responsible for the bulk of the observed effects on nitrogenase activity. In comparison, ADP-ribosylation in R. capsulatus was found to be relatively slow and incomplete but responded independently to both known stimuli, darkness and ammonium. Based on the in vitro nitrogenase activity of both the wild type and strains whose component II proteins cannot be ADP-ribosylated, it seems likely that the second response blocks either the ATP or the electron supply to nitrogenase.

[Psychological aspects observed during function rehabilitation of coronary patients]. / Aspects psychologiques observés au cours de la réadaptation fonctionnelle des coronariens

The authors have studied the influence of rehabilitation on the anxiety of 93 patients with myocardial infarction. The index of anxiety was measured objectively, as were the various primary factors. The change in these various factors has been favourable one in those patients who have had the benefit of complete rehabilitation. There seems to be a correlations between this change and the quality of rehabiltation as judged by the results of the exercise test which is undertaken at the end of it. Other psychological factors were also studied: the patient's estimate of his anxiety, of the rehabilitation, and of his own relationship to his illness, the factors which finally released his from the anxiety, and the features taken as a while.

Visibility and soiling: a comparison of the effects of leaded and unleaded gasolines.

The emissions from a fleet of late-model cars fueled with commercial, high-aromatic, unleaded gasoline caused nearly twice as much atmospheric light extinction as those from a matched fleet fueled with commercial, low-aromatic, leaded gasoline, when both were driven according to a consumer operating cycle in an idle traffic tunnel. The increased extinction and greater soiling potential result mainly from greater light absorption by the air-suspended particles from the unleaded fleet.