CT-based radiomics model with machine learning for predicting primary treatment failure in diffuse large B-cell Lymphoma

Biomarkers which can identify Diffuse Large B-Cell Lymphoma (DLBCL) likely to be refractory to first-line therapy are essential for selecting this population prior to therapy initiation to offer alternate therapeutic options that can improve prognosis. We tested the ability of a CT-based radiomics approach with machine learning to predict Primary Treatment Failure (PTF)-DLBCL from initial imaging evaluation. Twenty-six refractory patients were matched to 26 non-refractory patients, yielding 180 lymph nodes for analysis. Manual 3D delineation of the total node volume was performed by two independent readers to test the reproducibility. Then, 1218 hand-crafted radiomic features were extracted. The Random Forests machine learning approach was used as a classifier for constructing the prediction models. Seventy percent of the nodes were randomly assigned to a training set and the remaining 30% were assigned to an independent test set. The final model was tested on the dataset from the 2 readers, showing a mean accuracy, sensitivity and specificity of 73%, 62% and 82%, respectively, for distinguishing between refractory and non-refractory patients. The area under the receiver operating characteristic curve (AUC) was 0.83 and 0.79 for the two readers. We conclude that machine learning CT-based radiomics analysis is able to identify a priori PTF-DLBCL with a good accuracy.     

Anti-proliferative effects of a novel isoflavone derivative in medullary thyroid carcinoma: An in vitro study

Currently available treatments for patients with medullary thyroid carcinoma (MTC) with residual or recurrent disease after primary surgery have low efficacy rates. In view of the possible role of estrogen in the development of thyroid neoplasia, we explored whether proliferation of the human MTC TT cell line, might be curbed by carboxy-daidzein-tBoc (cD-tBoc), a novel isoflavone derivative. Estrogen receptor (ER) α mRNA expression in TT cells was more abundant than ERβ, with a ratio of 48:1. Estradiol-17β (E2) increased DNA synthesis in a dose dependent manner. [(3)H]-thymidine incorporation was also stimulated by the ERβ agonist DPN and the ERα agonist PPT. cD-tBoc inhibited TT cell growth as assessed by thymidine incorporation, XTT assay, and microscopic analysis of culture wells. Creatine kinase specific activity, a marker of the modulatory effects of estrogen on cell energy metabolism, was likewise inhibited. The inhibitory effect of cD-tBoc on [(3)H]-thymidine incorporation could be blocked by the ERβ antagonist PTHPP but not by the ERα antagonist MPP, suggesting that the antiproliferative effect of cD-tBoc on these cells is mediated through ERβ. Furthermore, cD-tBoc potently increased apoptosis and cell necrosis. Co-incubation with the antiapoptotic agent Z-VAD-FMK reversed the growth inhibitory effect elicited by cD-tBoc. These results support the hypothesis that estrogens are involved in the proliferation of MTC. The potent anti-proliferative effects mediated by isoflavone derivatives in the human MTC cell line TT suggest and that this property may be utilized to design effective anti-neoplastic agents.     

Systemic and anti-nociceptive effects of prolonged lidocaine,ketamine, and butorphanol infusions alone and in combination in healthy horses

Background

Prolonged drug infusions are used to treat horses with severe signs of pain, but can be associated with altered gastrointestinal transit. The purpose of this study was to determine the effects of prolonged constant rate infusions (CRI) of lidocaine (L), butorphanol (B), and ketamine (K) alone and in combination on gastrointestinal transit, behavior, and thermal nociceptive threshold in healthy horses.

Methods

Eight healthy adult horses were used in a randomized, cross-over, blinded, prospective experimental trial. Interventions were saline, L, K, B, LK, LB, BK, and LBK as an intravenous CRI for 96 hours. Drugs were mixed or diluted in saline; following a bolus, CRI rate was 0.15mL/kg/hr with drug doses as follows: L – 1.3 mg/kg then 3 mg/kg/hr; B – 0.018 mg/kg then 0.013 mg/kg/hr; K – 0.55 mg/kg then 0.5 mg/kg/hr. Two-hundred plastic beads were administered intragastrically by nasogastric tube immediately prior to the bolus. Feces were collected every 2 hours, weighed, and beads manually retrieved. Behavior was scored every 2 hours, vital parameters every 6 hours, and thermal nociceptive threshold every 12 hours for 96 hours. Drug concentrations in the LBK solution were tested every 6 hours for 72 hours.

Results

Four of 64 trials (3 LBK, 1 BK) were discontinued early due to signs of abdominal discomfort. There were no apparent differences between groups in vital parameters or thermal threshold. Transit time was delayed for LB and LBK with a corresponding decrease in fecal weight that was most severe in the final 24 hours of infusion. Significant changes in behavior scores, vital parameters, or thermal threshold were not observed. The concentration of each drug in the combined solution declined by less than 31% over the sampling period.

Conclusions

Drug combinations containing butorphanol cause an apparent delay in gastrointestinal transit in healthy horses without substantially affecting somatic nociception at the doses studied. Combinations of lidocaine and ketamine may have less impact on gastrointestinal transit than infusions combined with butorphanol. Further work is needed to determine the effects of these drugs in painful or critically ill patients.

     

A 660-Kb Deletion with Antagonistic Effects on Fertility and Milk Production Segregates at High Frequency in Nordic Red Cattle: Additional Evidence for the Common Occurrence of Balancing Selection in Livestock

In dairy cattle, the widespread use of artificial insemination has resulted in increased selection intensity, which has led to spectacular increase in productivity. However, cow fertility has concomitantly severely declined. It is generally assumed that this reduction is primarily due to the negative energy balance of high-producing cows at the peak of lactation. We herein describe the fine-mapping of a major fertility QTL in Nordic Red cattle, and identify a 660-kb deletion encompassing four genes as the causative variant. We show that the deletion is a recessive embryonically lethal mutation. This probably results from the loss of RNASEH2B, which is known to cause embryonic death in mice. Despite its dramatic effect on fertility, 13%, 23% and 32% of the animals carry the deletion in Danish, Swedish and Finnish Red Cattle, respectively. To explain this, we searched for favorable effects on other traits and found that the deletion has strong positive effects on milk yield. This study demonstrates that embryonic lethal mutations account for a non-negligible fraction of the decline in fertility of domestic cattle, and that associated positive effects on milk yield may account for part of the negative genetic correlation. Our study adds to the evidence that structural variants contribute to animal phenotypic variation, and that balancing selection might be more common in livestock species than previously appreciated.     

A new twist in trypanosome RNA metabolism: cis-splicing of pre-mRNA

It has been known for almost a decade and a half that in trypanosomes all mRNAs are trans-spliced by addition to the 5' end of the spliced leader (SL) sequence. During the same time period the conviction developed that classical cis-splicing introns are not present in the trypanosome genome and that the trypanosome gene arrangement is highly compact with small intergenic regions separating one gene from the next. We have now discovered that these tenets are no longer true. Poly(A) polymerase (PAP) genes in Trypanosoma brucei and Trypanosoma cruzi are split by intervening sequences of 653 and 302 nt, respectively. The intervening sequences occur at identical positions in both organisms and obey the GT/AG rule of cis-splicing introns. PAP mRNAs are trans-spliced at the very 5' end as well as internally at the 3' splice site of the intervening sequence. Interestingly, 11 nucleotide positions past the actual 5' splice site are conserved between the T. bruceiand T. cruzi introns. Point mutations in these conserved positions, as well as in the AG dinucleotide of the 3' splice site, abolish intron removal in vivo. Our results, together with the recent discovery of cis-splicing introns in Euglena gracilis, suggest that both trans- and cis-splicing are ancient acquisitions of the eukaryotic cell.     

Accumulation of CK-MM is impaired in innervated and contracting cultured muscle fibers of Duchenne muscular dystrophy patients

No specific abnormalities have been reproducibly manifested in aneurally cultured muscle of Duchenne muscular dystrophy (DMD) patients. We now report that the accumulation of the muscle-"specific" isozyme of creatine kinase (CK-MM) was significantly and preferentially impaired in long-term innervated contracting muscle fibers cultured from 4 DMD patients (DMD-InnCMFs) compared to: i) their noninnervated sister-cultured muscle fibers, and ii) innervated contracting control cultured human muscle fibers (Control-InnCHMFs). Accumulation of other muscle-"specific" isozymes (MSIs), viz. glycogen phosphorylase, phosphoglycerate mutase, and lactic dehydrogenase, was not significantly impaired. We have not observed preferentially-impaired CK-MM accumulation in any Control-InnCHMFs from 22 patients (children and adults) with a variety of neuromuscular diseases. There was no apparent difference between DMD-InnCMFs and Control InnCHMFs regarding: acceptance of innervation; neuronally-driven, virtually continuous muscle-fiber contractions; characteristic myofiber organization by phase-contrast microscopy, and increased longevity of the innervated fibers.     

Über die Wirkungsweise der Herznerven bei den Fischen. V.

Zusammenfassung Bei den Fischherzen vom Typus A, die man bei den Aalen findet, äußert sich die erste Wirkung des Vagus in einer Verlängerung der refraktären Phase der Überleitungsgebilde zwischen Sinus und Vorhof. Der Sinus arbeitet zumeist in unverminderter Frequenz und unveränderter Kraft weiter, die übrigen Herzabteilungen, Vorhof und Kammer sind noch erregbar, die Ursprungsantriebe, die vom Sinus ihren Ausgang nehmen, können aber nicht in voller Zahl oder überhaupt nicht mehr auf den Vorhof übertragen werden.Zumeist macht sich neben der Blockierung der Überleitung zwischen Sinus und Vorhof auch eine negativ inotrope Wirkung am Vorhof bemerkbar. Diese ist für die Stillegung des zweiten Automatiezehtrums im Ohrkanal von wesentlicher Bedeutung.Eine Verstärkung des Vagusreizes führt eine Verlangsamung der Tätigkeit des Sinus herbei. Bei ganz starken Vaguserregungen wird auch der Sinus stillgelegt, es tritt also ein Stillstand des ganzen Herzens ein.Nach wiederholter Vagusreizung läßt die Wirkung auf die Überleitungsgebilde zwischen Sinus und Vorhof nach, es macht sich dann vorzugsweise eine negativ inotrope Beeinflussung der Tätigkeit des Vorhofes sowie eine Störung an den Überleitungsgebilden zwischen Vorhof und Kammer bemerkbar. Diese äußert sich in der gleichen Weise wie an den Überleitungsfasern zwischen Sinus und Vorhof durch eine allmähliche Verlängerung der refraktären Phase.Ein Unterschied zwischen der Wirkung des rechten und linken Vagus ist nicht nachweisbar.Als Nachwirkung fällt vorzugsweise eine negativ inotrope Beeinflussung der Vorhofstätigkeit auf. Eine Frequenzänderung ist nahezu niemals zu beobachten. Gelegentlich machen sich im Gefolge einer Vaguserregung Störungen der Herztätigkeit bemerkbar.Die vorliegende Untersuchung wurde mit Hilfe einer Spende der Medizinischen Fakultät der Thüringischen Landesuniversität Jena durchgeführt, der auch an dieser Stelle herzlichst gedankt sein soll.     

Comparative study of the AT(1) receptor prodrug antagonist candesartan cilexetil with other sartans on the interactions with membrane bilayers

Drug-membrane interactions of the candesartan cilexetil (TCV-116) have been studied on molecular basis by applying various complementary biophysical techniques namely differential scanning calorimetry (DSC), Raman spectroscopy, small and wide angle X-ray scattering (SAXS and WAXS), solution (1)H and (13)C nuclear magnetic resonance (NMR) and solid state (13)C and (31)P (NMR) spectroscopies. In addition, (31)P cross polarization (CP) NMR broadline fitting methodology in combination with ab initio computations has been applied. Finally molecular dynamics (MD) was applied to find the low energy conformation and position of candesartan cilexetil in the bilayers. Thus, the experimental results complemented with in silico MD results provided information on the localization, orientation, and dynamic properties of TCV-116 in the lipidic environment. The effects of this prodrug have been compared with other AT(1) receptor antagonists hitherto studied. The prodrug TCV-116 as other sartans has been found to be accommodated in the polar/apolar interface of the bilayer. In particular, it anchors in the mesophase region of the lipid bilayers with the tetrazole group oriented toward the polar headgroup spanning from water interface toward the mesophase and upper segment of the hydrophobic region. In spite of their localization identity, their thermal and dynamic effects are distinct pointing out that each sartan has its own fingerprint of action in the membrane bilayer, which is determined by the parameters derived from the above mentioned biophysical techniques.     

Validation of an Instrument to Measure Older Adults' Expectations Regarding Movement (ERM)

Background

Many individuals with Parkinson''s disease are not diagnosed and treated. Attitudes about aging and related help-seeking may affect the timely diagnosis of Parkinson''s disease. Our objectives were to develop measures of older adults'' expectations regarding movement with aging, specifically related to parkinsonism, and their beliefs about seeking healthcare for the diagnosis and treatment of parkinsonism.

Methods

We established content and face validity from interviews with experts, review of the literature, and pre-testing with key informants. Two 9-item instruments resulted: Expectations Regarding Movement (ERM) and Healthcare Seeking Beliefs for parkinsonism (HSB). These instruments were administered to 210 older adults at senior centers to investigate internal consistency and construct validity.

Results

192 (91%) of the older adults completed more than 90% of the survey. The mean age was 76; 17 (9%) reported parkinsonism. Both scales demonstrated good internal consistency (α = 0.90). Factor analysis supported construct validity of the ERM and HSB scores. Older age, lower education, worse self-reported health and African American race each were associated with lower ERM scores, but not HSB scores.

Conclusion

The ERM, a brief measure of expectations regarding movement with aging, shows reliability and validity. This scale may be useful in identifying older adults at increased risk for under-identification of Parkinson''s disease. Further work is needed to measure healthcare seeking for parkinsonism.