HPV circulating tumor DNA to monitor the efficacy of anti‐PD‐1 therapy in metastatic squamous cell carcinoma of the anal canal: A case report

Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV‐associated cancer with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab, an anti PD‐1 immune checkpoint inhibitor, demonstrated significant efficacy as single‐agent therapy in metastatic SCCA patients. Nevertheless, imaging assessment by standard RECIST criteria of the efficacy of immune therapy can be difficult in some patients due to tumor immune cell infiltration, and biomarkers of treatment efficacy are needed. We have previously developed a quantitative droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV ctDNA), with excellent sensitivity and specificity. Here, we report, for the first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic SCCA, who obtained sustained partial response to single‐agent nivolumab. We observed an early and very significant decrease of HPV ctDNA during therapy from the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks, and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides proof‐of‐concept that HPV ctDNA can be used as a noninvasive early dynamic biomarker to monitor the efficacy of new immunotherapy agents.     

Central effects of isolated fractions from the root of Petiveria alliacea L. (tipi) in mice

Ethnopharmacological relevance

Petiveria alliacea L. (tipi) a shrub from Phytolaccaceae family is popularly used in folk medicine for treating a wide variety of disorders in South and Central America.

Aim of the study

To investigate the neuropharmacological properties on experimental animals.

Materials and methods

The acetate (FA), hexanic (FH), hydroalcoholic (FHA) and precipitated hydroalcoholic (FHAppt) fractions from the root of tipi were studied to investigate its pharmacological properties in the classical behavioral models (open-field, elevated plus maze-EPM, rotarod, barbiturate-induced sleeping time, forced swimming and pentylenetetrazole (PTZ)-induced convulsions tests) using mice. These fractions were administered intraperitoneally and orally to female mice at single doses of 100 and 200 mg/kg.

Results

All these fractions decreased the locomotor activity, rearing and grooming in the open-field test, suggesting a possible central depressant action. No significant effect was evident on motor coordination of the animals in the rotarod test. On EPM, all the fractions of tipi presented a significant reduction on the time of permanence in the open arms, indicating an absence of anxiolytic-like effect. In addition, the fractions increased the immobility time in the forced swimming test and potentiated pentobarbital-induced sleeping time in mice, confirmed a probable sedative and central depressant effect. Furthermore, the fractions increased the latency to the first convulsion and the lethal time of the PTZ-induced convulsions test in the animals, confirmed its popular use as anticonvulsant.

Conclusion

Our results suggest that the fractions of P. alliacea L. contains biologically active substance(s) that might be acting in the CNS and have significant depressant and anticonvulsant potentials, supporting folk medicine use of this plant.     

Travel-Associated Rabies in Pets and Residual Rabies Risk,Western Europe

In 2015, countries in western Europe were declared free of rabies in nonflying mammals. Surveillance data for 2001–2013 indicate that risk for residual rabies is not 0 because of pet importation from countries with enzootic rabies. However, the risk is so low (7.52 × 10⁻¹⁰) that it probably can be considered negligible.     

Impact de l’utilisation de valves bidirectionnelles sur la qualité des séances en hémodialyse chronique

Luer access valves are medical devices used to reduce infectious risks by securing repetitive handling in chronic hemodialysis using central catheter. Their impact on the effectiveness of a hemodialysis session still remains poorly studied. This in vivo study aims to evaluate its effectiveness. Tego^® and Q-Syte^® valves were used in alternation for each patient for four weeks (428 hemodialysis sessions). The two-luer access valves have led to a significant increase in the dysfunction of the hemodialysis sessions (51.8% compared to the usual care (39.3%) (P = 0.012). The analysis by sub-category suggests a heterogeneous behavior of the two devices. The Q-Syte^® valve showed significantly more dysfunction than the Tego^® valve or the absence of valve. However, both valve systems tested can maintain the performance of the hemodialysis session as they don’t change the dose of dialysis. This study highlights that an evaluation of each device must be performed prior to their use to assess the risk-benefit balance.     

Differences between hospitals in attainment of parathyroid hormone treatment targets in chronic kidney disease do not reflect differences in quality of care

ABSTRACT: BACKGROUND: Transparency in quality of care (QoC) is stimulated and hospitals are compared and judged on the basis of indicators of performance on specific treatment targets. In patients with chronic kidney disease, QoC differed significantly between hospitals. In this analysis we explored additional parameters to explain differences between centers in attainment of parathyroid hormone (PTH) treatment targets. METHODS: Using MASTERPLAN baseline data, we selected one of the worst (center A) and one of the best (center B) performing hospitals. Differences between the two centers were analyzed from the year prior to start of the MASTERPLAN study until the baseline evaluation. Determinants of PTH were assessed. RESULTS: 101 patients from center A (median PTH 9.9 pmol/l, in 63 patients exceeding recommended levels) and 100 patients from center B (median PTH 6.5 pmol/l, in 32 patients exceeding recommended levels), were included. Analysis of clinical practice did not reveal differences in PTH management between the centers. Notably, hyperparathyroidism resulted in a change in therapy in less than 25% of patients. In multivariate analysis kidney transplant status, MDRD-4, and treatment center were independent predictors of PTH. However, when MDRD-6 (which accounts for serum urea and albumin) was used instead of MDRD-4, the center effect was reduced. Moreover, after calibration of the serum creatinine assays treatment center no longer influenced PTH. CONCLUSIONS: We show that differences in PTH control between centers are not explained by differences in treatment, but depend on incomparable patient populations and laboratory techniques. Therefore, results of hospital performance comparisons should be interpreted with great caution.     

Post-PKS Tailoring Steps of the Spiramycin Macrolactone Ring in Streptomyces ambofaciens

Spiramycins are clinically important 16-member macrolide antibiotics produced by Streptomyces ambofaciens. Biosynthetic studies have established that the earliest lactonic intermediate in spiramycin biosynthesis, the macrolactone platenolide I, is synthesized by a type I modular polyketide synthase (PKS). Platenolide I then undergoes a series of post-PKS tailoring reactions yielding the final products, spiramycins I, II, and III. We recently characterized the post-PKS glycosylation steps of spiramycin biosynthesis in S. ambofaciens. We showed that three glycosyltransferases, Srm5, Srm29, and Srm38, catalyze the successive attachment of the three carbohydrates mycaminose, forosamine, and mycarose, respectively, with the help of two auxiliary proteins, Srm6 and Srm28. However, the enzymes responsible for the other tailoring steps, namely, the C-19 methyl group oxidation, the C-9 keto group reduction, and the C-3 hydroxyl group acylation, as well as the timing of the post-PKS tailoring reactions, remained to be established. In this study, we show that Srm13, a cytochrome P450, catalyzes the oxidation of the C-19 methyl group into a formyl group and that Srm26 catalyzes the reduction of the C-9 keto group, and we propose a timeline for spiramycin-biosynthetic post-PKS tailoring reactions.     

The effect of cooling on muscle co-ordination in spasticity: assessment with the repetitive movement test

Purpose: Cooling muscles might produce a temporary reduction of spasticity. This study investigated muscle coordination in spasticity under the influence of cooling. Methods: A repetitive movement (RM-) test of the ankle was used, while measuring the angle and surface-electromyography (EMG) of the m. tibialis anterior and m. triceps surae. Ensemble averaging provided quantified measures of muscle activation. Sixteen patients with spasticity in their lower extremity due to stroke or spinal cord injury participated in the study. Physical examination and the RM-test was done before and after cooling the m. triceps surae for 20 minutes by coldpacks. Results: The results show that Achilles hyperreflexia and clonus were abolished in all, and all but one patient, respectively. The EMG of the m. triceps surae, acting as a prime mover, was increased (p 0.028). However, this improved muscle coordination resulted in just a slightly increased active range of motion (less than 2 degrees at p 0.049). Conclusion: Apparently, the increase in excitability of the alpha motoneuron pool in voluntary movements of patients with spasticity is not followed by an improvement in the ability to move.     

Aging-related Decrease of Human ASC Angiogenic Potential Is Reversed by Hypoxia Preconditioning Through ROS Production

Adipose stroma/stem cells (ASC) represent an ideal source of autologous cells for cell-based therapy. Their transplantation enhances neovascularization after experimental ischemic injury. Aging is associated with a progressive decrease in the regenerative potential of mesenchymal stem cells (MSCs) from bone marrow. This work aims to determine the aging effect on human ASC capacities. First, we show that aging impairs angiogenic capacities of human ASC (hASC) in a mouse ischemic hindlimb model. Although no change in hASC number, phenotype, and proliferation was observed with aging, several mechanisms involved in the adverse effects of aging have been identified in vitro combining a concomitant decrease in (i) ASC ability to differentiate towards endothelial cells, (ii) secretion of proangiogenic and pro-survival factors, and (iii) oxidative stress. These effects were counteracted by a hypoxic preconditioning that improved in vivo angiogenic capacities of hASC from older donors, while hASC from young donors that have a strong ability to manage hypoxic stress were not. Finally, we identified reactive oxygen species (ROS) generation as a key signal of hypoxia on hASC angiogenic capacities. This study demonstrates for the first time that age of donor impaired angiogenic capacities of hASC in ischemic muscle and change in ROS generation by hypoxic preconditioning reverse the adverse effect of aging.