Model-based evaluation of the efficacy and safety of nivolumab once every 4 weeks across multiple tumor types.

BACKGROUND: Nivolumab 480 mg every 4 weeks (Q4W) is approved in the European Union, United States, and several other markets across multiple tumor types. Its approval was supported by quantitative efficacy/safety analyses bridging to 3 mg/kg every 2 weeks (Q2W). PATIENTS AND METHODS: The benefit-risk profile of nivolumab 480 mg Q4W relative to 3 mg/kg Q2W was evaluated using population pharmacokinetic modeling and exposure-response (E-R) analyses for safety and efficacy. Pharmacokinetic exposures were predicted for 3203 patients with melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), squamous cell carcinoma of the head and neck, urothelial carcinoma, or classical Hodgkin lymphoma. Quantitative models analyzed E-R to predict 480-mg Q4W safety across all indications and efficacy for melanoma, NSCLC, and RCC. Intratumoral receptor occupancy (RO) was predicted for parameters representing different tumor types. RESULTS: Time-averaged concentrations for 480 mg Q4W versus 3 mg/kg Q2W were higher during the first 28 days (26.8%) and similar at steady state (5.2%). The maximum concentration (Cmax) after the first dose was higher (110.4%), and the trough concentration at day 28 was lower (-22.1%) with 480 mg Q4W versus 3 mg/kg Q2W. The Cmax achieved with 480 mg Q4W was lower than the previously established safe dose of 10 mg/kg Q2W. The probability of adverse events for key safety end points was similar for 480 mg Q4W and 3 mg/kg Q2W. The predicted overall survival and objective response rates with 480 mg Q4W were comparable to 3 mg/kg Q2W. The predicted high intratumoral RO provided additional evidence to support 480 mg Q4W across tumor types. CONCLUSIONS: The benefit-risk profile for nivolumab 480 mg Q4W was predicted to be similar to that of 3 mg/kg Q2W across tumor types while providing a convenient and flexible option for patients and their caregivers.

Quantitative Systems Pharmacology: A Case for Disease Models.

Quantitative systems pharmacology (QSP) has emerged as an innovative approach in model-informed drug discovery and development, supporting program decisions from exploratory research through late-stage clinical trials. In this commentary, we discuss the unique value of disease-scale "platform" QSP models that are amenable to reuse and repurposing to support diverse clinical decisions in ways distinct from other pharmacometrics strategies.

Systems biology for simulating patient physiology during the postgenomic era of medicine.

Systems pharmacology models capable of accurately recapitulating sophisticated patient phenotypes have enabled the investigation of mechanisms responsible for therapeutic efficacy. Although omics data sets are capable of characterizing the operation of subcellular networks, their utility in mechanistically predicting quantitative, clinically accessible outcome measures has been limited. Developing insights into clinical outcomes from omics data sets will benefit from modeling approaches that can integrate molecular networks mechanistically with simulations of patient pathophysiology across compartments and scales.

Evaluation of current approaches to stream classification and a heuristic guide to developing classifications of integrated aquatic networks.

Conservation and management of fresh flowing waters involves evaluating and managing effects of cumulative impacts on the aquatic environment from disturbances such as: land use change, point and nonpoint source pollution, the creation of dams and reservoirs, mining, and fishing. To assess effects of these changes on associated biotic communities it is necessary to monitor and report on the status of lotic ecosystems. A variety of stream classification methods are available to assist with these tasks, and such methods attempt to provide a systematic approach to modeling and understanding complex aquatic systems at various spatial and temporal scales. Of the vast number of approaches that exist, it is useful to group them into three main types. The first involves modeling longitudinal species turnover patterns within large drainage basins and relating these patterns to environmental predictors collected at reach and upstream catchment scales; the second uses regionalized hierarchical classification to create multi-scale, spatially homogenous aquatic ecoregions by grouping adjacent catchments together based on environmental similarities; and the third approach groups sites together on the basis of similarities in their environmental conditions both within and between catchments, independent of their geographic location. We review the literature with a focus on more recent classifications to examine the strengths and weaknesses of the different approaches. We identify gaps or problems with the current approaches, and we propose an eight-step heuristic process that may assist with development of more flexible and integrated aquatic classifications based on the current understanding, network thinking, and theoretical underpinnings.

Subacute delayed ascending myelopathy after low spine injury: case report and evidence of a vascular mechanism.

STUDY DESIGN: Case report of a patient with subacute delayed myelopathy after an acute low thoracic spine injury. OBJECTIVES: To draw awareness to a rarely described complication with potential to add devastating neurological insult to the original spinal cord injury, and to discuss evidence supporting a vascular mechanism. SETTING: Health Science Centre, Winnipeg, Manitoba, Canada. CASE REPORT: A 35-year-old woman developed clinical and MRI evidence of ascending myelopathy, extending up to C5, 16 days after a T11/12 fracture dislocation. The distribution of MRI signal abnormality, MRI evidence of prominent venous markings, and association with upright mobilization and the wearing of a thoraco-lumbo-sacral orthosis, suggest that elevated spinal venous pressure in conjunction with low arterial pressure may have induced impaired spinal cord vascular perfusion. CONCLUSION: After recent spinal cord injury, factors exacerbating spinal venous hypertension and/or arterial hypotension may in some patients lead to impaired spinal cord perfusion. These factors should be considered and corrected if symptoms or signs of progressive myelopathy emerge in the first few days or weeks after injury.

Voltage-sensitivity of motoneuron NMDA receptor channels is modulated by serotonin in the neonatal rat spinal cord.

Both N-methyl-D-aspartate (NMDA) and serotonin (5-HT) receptors contribute to the generation of rhythmic motor patterns in the rat spinal cord. Co-application of these chemicals is more effective at producing locomotor-like activity than either neurochemical alone. In addition, NMDA application to rat spinal motoneurons, synaptically isolated in tetrodotoxin, induces nonlinear membrane behavior that results in voltage oscillations which can be blocked by 5-HT antagonists. However, the mechanisms underlying NMDA and 5-HT receptor interactions pertinent to motor rhythm production remain to be determined. In the present study, an in vitro neonatal rat spinal cord preparation was used to examine whether NMDA receptor-mediated nonlinear membrane voltage is modulated by 5-HT. Whole-cell recordings of spinal motoneurons demonstrated that 5-HT shifts the region of NMDA receptor-dependent negative slope conductance (RNSC) of the current-voltage relationship to more hyperpolarized potentials and enhances whole-cell inward current. The influence of 5-HT on the RNSC was similar to the effect on the RNSC of decreasing the extracellular Mg(2+)concentration. The results suggest that 5-HT may modulate this form of membrane voltage nonlinearity by regulating Mg(2+) blockade of the NMDA ionophore.

A framework for care during the stroke experience.

This article describes a model we developed to guide the selection and design of nursing activities that will facilitate the health of persons with stroke and their families. Care in the context of stroke has been structured by the medical model's focus on functional ability. As a result, nursing is viewed as ancillary to other professions; yet, studies of the stroke experience from the patient's view suggest that distinctive nursing interventions are needed. Current models of illness do not sufficiently address the nature of stroke and thus cannot serve as a framework for nursing care. Our model conceptualizes stroke as a progressive, holistic experience with physiological, psychological, and social dimensions. It was developed from a synthesis of research articles identified through searches of CINAHL, MEDLINE, and PSYCHLIT (1980-1999) indexes using the terms "stroke," "stress," "coping," "chronic illness," and "transitions and growth" and from our clinical experiences. Our research established that the stroke experience involves the deterioration of the whole person and the development of a new person through discovery and resynthesis. Each of these processes progressively dominates the experience and together they form a three-phase model. This model of the stroke experience suggests that nursing care should focus initially on limiting deterioration and then concentrate on facilitating growth. Selection of specific interventions requires an understanding of the uniqueness of each stroke experience, as well as the commonalities, among these experiences.

The role of serotonin in reflex modulation and locomotor rhythm production in the mammalian spinal cord.

Over the past 40 years, much has been learned about the role of serotonin in spinal cord reflex modulation and locomotor pattern generation. This review presents an historical overview and current perspective of this literature. The primary focus is on the mammalian nervous system. However, where relevant, major insights provided by lower vertebrate models are presented. Recent studies suggest that serotonin-sensitive locomotor network components are distributed throughout the spinal cord and the supralumbar regions are of particular importance. In addition, different serotonin receptor subtypes appear to have different rostrocaudal distributions within the locomotor network. It is speculated that serotonin may influence pattern generation at the cellular level through modulation of plateau properties, an interplay with N-methyl-D-aspartate receptor actions, and afterhyperpolarization regulation. This review also summarizes the origin and maturation of bulbospinal serotonergic projections, serotonin receptor distribution in the spinal cord, the complex actions of serotonin on segmental neurons and reflex pathways, the potential role of serotonergic systems in promoting spinal cord maturation, and evidence suggesting serotonin may influence functional recovery after spinal cord injury.

Nutritional evaluation of children with phenylketonuria.

CONTEXT: Dietary phenylalanine (PA) restriction is the most effective form for reducing its excess in the blood and is the only efficient method for treating phenylketonuria. The diet is complex and should be adapted to combine the patients' eating habits, growth and development. It depends basically on the use of industrialized products as substitutes free of PA for proteins that are not fully supplied. OBJECTIVE: To evaluate the nutritional status of children with phenylketonuria (PKU) by anthropometric measurements and food intake. DESIGN: Cross-sectional study. SETTING: Children with PKU attending the Association of Parents and Friends of Handicapped Children (Associação de Pais e Amigos dos Excepcionais - APAE) and normal children attending at municipal day care centers in São Paulo. PARTICIPANTS: 42 children with PKU and 31 normal children aged 1 to 12 of both sexes were assessed in two groups, under and over 7 years of age. MAIN MEASUREMENTS: Weight and height measurements. RESULTS: Children with PKU ingested calories, calcium, iron, zinc, and copper below the recommended values, whereas the protein intake was within the normal range. Food intake in the group of normal children was within normality rates. The height/weight Z-score means for children with PKU were 0.47 for those under 7 years and 1.86 for 7 year-olds and over; in normal children the means were 0.97 <7 years and 1.54 >/=7 years, with no statistically significant difference. The height/age Z-score means were significantly lower in the PKU children <7 years (-1.23) than in the normal controls (0.91). CONCLUSIONS: The data presented demonstrate the importance of nutritional surveillance in patients with PKU so as to support adequacy of nutrient intake and to guarantee growth within the relevant standards.

Plasma zinc, copper, and erythrocyte superoxide dismutase in children with phenylketonuria.

Children with phenylketonuria (PKU) are treated with semisynthetic diets restricted in phenylalanine (PHE). The formulae must supply those trace elements and vitamins that are usually supplied by whole protein foods. We studied the effects of phenylalaline restricted diets in 42 children with PKU (P) and 31 normal (N) children, aged 1-12 y, divided into two groups (below and above 7 y). Plasma zinc and copper were analyzed by means of atomic spectrophotometry, and superoxide dismutase (CuZnSOD) activity was measured in erythrocytes, through NBT inhibition and its profile, as determined by isoelectric focalization. Plasma zinc of PKU children > or = 7 years old was significantly lower than that in the control group (17 mumol/L versus 20 mumol/L) but still within the normal range; in children < 7 years no substantial differences were found between the two groups. Plasma copper was not statistically different between PKU and normal children. Qualitative activity of CuZnSOD presented the same electrophoretic profile in both normal and PKU. Quantitative activity was not different in both P (1210 U/g Hb < 7 versus 1328 U/g hemoglobin (Hb) > or = 7) and N (1675 U/g Hb < 7 versus 1367 U/g Hb > or = 7). We concluded that children with PKU presented normal mean levels of zinc and copper, with preserved function, measured by enzyme activity.

NMDA receptor-mediated oscillatory activity in the neonatal rat spinal cord is serotonin dependent.

The effect of serotonin (5-HT) receptor blockade on rhythmic network activity and on N-methyl--aspartate (NMDA) receptor-induced membrane voltage oscillations was examined using an in vitro neonatal rat spinal cord preparation. Pharmacologically induced rhythmic hindlimb activity, monitored via flexor and extensor electroneurograms or ventral root recordings, was abolished by 5-HT receptor antagonists. Intrinsic motoneuronal voltage oscillations, induced by NMDA in the presence of tetrodotoxin (TTX), either were abolished completely or transformed to long-lasting voltage shifts by 5-HT receptor antagonists. Conversely, 5-HT application facilitated the expression of NMDA-receptor-mediated rhythmic voltage oscillations. The results suggest that an interplay between 5-HT and NMDA receptor actions may be critical for the production of rhythmic motor behavior in the mammalian spinal cord, both at the network and single cell level.

Whole cell recordings of lumbar motoneurons during locomotor-like activity in the in vitro neonatal rat spinal cord.

Whole cell current- and voltage-clamp recordings were obtained from lumbar motoneurons in the isolated neonatal rat spinal cord to characterize the behavior of motoneurons during neurochemically induced locomotor-like activity. Bath application of serotonin (10-100 muM) in combination with N-methyl-D-aspartate (1-12 muM) initially produced tonic membrane depolarization (mean = 26 mV), increased input resistance, decreased rheobase, and increased spike inactivation in response to depolarizing current pulse injections. After the initial tonic depolarization, rhythmic fluctuations of the motoneuron membrane potential (locomotor drive potentials; LDPs) developed that were modulated phasically in association with ventral root discharge. The peak and trough voltage levels of the LDP fluctuated above and below the membrane potential recorded immediately before the onset of rhythmic activity. Similarly, firing frequency was modulated above and below prelocomotion firing rates (in those motoneurons that displayed neurochemically induced tonic firing immediately before the onset of rhythmic activity). These observations are consistent with an alternation between phasic excitatory and inhibitory synaptic drives. The amplitude of LDPs and rhythmic excitatory drive current increased with membrane depolarization from -80 to -40 mV and then decreased with further depolarization, thus displaying nonlinear voltage-dependence. Faster frequency, small amplitude voltage fluctuations were observed superimposed on the depolarized phase of LDPs. In some motoneurons, the trajectory of these superimposed fluctuations was consistent with a synaptic origin, whereas in other cells, the regular sinusoidal appearance of the fluctuations and the occurrence of superimposed plateau potentials were more compatible with the activation of an intrinsic membrane property. One motoneuron displayed exclusively excitatory phasic drive, and another motoneuron was characterized by inhibitory phasic drive alone, during rhythmic activity. These findings are compatible with the concept of a central pattern generator that is capable of delivering both excitatory and inhibitory drive to motoneurons during locomotion. The data also suggest that the rhythmic excitatory and inhibitory outputs of the hypothetical half-center model can be dissociated and operate in isolation.

NMDA receptor-mediated oscillatory properties: potential role in rhythm generation in the mammalian spinal cord.

Previous studies have demonstrated that (1) NMDA receptor activation occurs during locomotor network operation in lower and higher vertebrates and (2) NMDA induces active membrane properties that can be expressed as intrinsic voltage fluctuations in cells located in the spinal cord of lower vertebrates, as well as in neurons located in supraspinal regions of the mammalian nervous system. This paper reviews recent data showing that NMDA can induce similar inherent membrane potential behavior in synaptically isolated motoneurons and interneurons in the mammalian (in vitro neonatal rat) spinal cord. These TTX-resistant voltage fluctuations include rhythmic oscillations and plateau potentials, as well as low-frequency long-lasting voltage shifts (LLVSs). 5-HT facilitates the transformation of LLVSs into oscillatory events, and 5-HT receptor antagonists have the reverse effect. In the absence of TTX, locomotor-related rhythmic drive potentials in spinal cord neurons can display nonlinear voltage behavior compatible with NMDA receptor activation, although other voltage-activated conductances are not excluded. Suppression of the nonlinear voltage response associated with NMDA receptor activation, via removal of Mg2+, disrupts locomotor patterns of network activity. The potential role of NMDA receptor activation in the operation of mammalian locomotor networks is discussed in the context of these recent observations.

IFN-gamma inducibility of class II transactivator is specifically lacking in human tumour lines: relevance to retinoblastoma protein rescue of IFN-gamma inducibility of the HLA class II genes.

We have previously reported that HLA class II induction by IFN-gamma is rescuable by reconstitution of functional retinoblastoma protein (RB) in two RB-defective tumour lines: the breast carcinoma line, MDA-468-S4 (S4) and the non-small cell lung carcinoma line, H2009. To determine the range of tumours and tumour types in which RB rescues HLA class II inducibility, we examined another RB-defective tumour line, the retinoblastoma line, WERI-Rb1. As in the case of S4 and H2009, HLA-DRA and -DRB were non-inducible by IFN-gamma in WERI-Rb1. However, neither inducibility of DRA nor DRB mRNA was resulted in an RB-positive stable transformant of WERI-Rb1, WLRB-8. While guanylate-binding protein (GBP) inducibility indicated that the basic IFN-gamma signal transduction pathway remained intact in WERI-Rb1, mRNA for class II transactivator (CIITA), a mediator of the IFN-gamma activation of the HLA class II genes and several other genes related to immune function, was not detectable in IFN-gamma-treated WERI-Rb1, indicating that the lack of CIITA expression was responsible, at least in part, for the inability of RB to rescue HLA class II-inducibility. The HLA class II-associated invariant chain (Ii), the expression of which is also up-regulated by CIITA, was non-inducible in WERI-Rb1, consistent with non-inducible CIITA. Also, IFN-gamma failed to activate the DRA, DRB and Ii promoters in WERI-Rb1. However, exogenous CIITA expression in WERI-Rb1 activated the DRA, DRB and Ii promoter-chloramphinocol acetyltransferase constructs, confirming that CIITA was not induced in WERI-Rb1 and indicating that other proteins required for activation of the class II and Ii promoters were functional in this cell line. Examination of additional cell lines for GBP and CIITA induction revealed that a specific lack of the CIITA IFN-gamma response is common in human tumour lines. The possible role of CIITA defects in tumorigenesis is discussed.

Regional distribution of the locomotor pattern-generating network in the neonatal rat spinal cord.

The regional distribution of spinal cord networks producing locomotor-like, as well as non-locomotor-like, activity was studied with the use of an in vitro neonatal rat preparation. Rhythmic activity was induced by bath application of either serotonin (5-HT), acetylcholine (ACh), N-methyl-D,L-aspartate (NMA), or combined 5-HT/NMA, and was monitored via hindlimb flexor (peroneal) and extensor (tibial) electroneurograms (ENGs) or ventral root recordings. In some experiments, synchronous patterns were produced by the addition of inhibitory amino acid (IAA) receptor antagonists. Selective application of 5-HT to cervical and thoracic cord regions induced rhythmic activity in these segments but failed to evoke hindlimb ENG discharge. Exposure of the isolated lumbar region to 5-HT produced tonic activity only. Application of 5-HT to the whole cord produced locomotor-like activity in hindlimb ENGs that persisted after midsagittal section of the spinal cord from the conus to the thoracolumbar junction. In other experiments, transverse hemisection of the rostral lumbar cord during whole cord exposure to 5-HT abolished rhythmic activity in ipsilateral hindlimb ENGs, suggesting that under these conditions rhythmic activity on one side of the lumbar cord was insufficient to maintain rhythmic activity on the contralateral side. Selective application of NMA or ACh to cervical and/or thoracic cord regions evoked rhythmic activity in these supralumbar segments, as well as rhythmic, but non-locomotor-like, activity in the lumbar region. In contrast to the effect of 5-HT, both NMA and ACh evoked rhythmic activity when applied solely to the lumbar region, and the side-to-side alternation produced by whole cord ACh application was uncoupled by midsagittal lesions of the lumbar region. In the presence of IAA antagonists, the side-to-side coupling of bilaterally synchronous rhythms was maintained despite extensive midsagittal lesions leaving all but one or two segments of either cervical, thoracic, or lumbar cord bilaterally intact, and rhythmic activity could be maintained even in single isolated hemisegments. The effects of 5-HT/NMA were similar to those observed with the use of 5-HT alone, although 5-HT/NMA induced rhythmic activity in hindlimb ENGs when applied selectively to supralumbar regions. The results suggest that 1) a 5-HT-sensitive oscillatory network, capable of producing a locomotor-like pattern of activity, is distributed throughout the supralumbar region of the spinal cord and mediates descending rhythmic drive to lumbar motor centers; 2) NMA- and ACh-sensitive rhythmogenic elements are distributed throughout the spinal cord, including the lumbar region; and 3) the spinal cord contains an extensive propriospinal network of reciprocal inhibitory and excitatory connections characterized by redundantly organized side-to-side projections.

NMDA receptor activation triggers voltage oscillations, plateau potentials and bursting in neonatal rat lumbar motoneurons in vitro.

Whole-cell recordings of lumbar motoneurons in the intact neonatal rat spinal cord in vitro were undertaken to examine the effects of N-methyl-D-aspartate (NMDA) receptor activation on membrane behaviour. Bath application of NMDA induced rhythmic voltage oscillations of 5.9+/-2.1 mV (SD) at a frequency of 4.4+/-1.5 Hz. Amplitude, but not frequency, of the voltage oscillations was membrane potential-dependent. Voltage oscillations could recruit action potentials and/or plateau potentials with or without superimposed bursting. Blockade of synaptic transmission with tetrodotoxin (TTX) sometimes resulted in a loss of oscillatory activity which could then be restored by increasing the NMDA concentration. After application of TTX, the trajectory of NMDA-induced oscillations was similar to the trajectory induced in the presence of intact synaptic networks, although the mean oscillation duration was longer and the oscillation frequency was slower (1.8+/-1.1 Hz). Current ramps delivered after bath application of NMDA demonstrated bistable membrane properties which may underlie the plateau potentials. Injection of intracellular current pulses could initiate, entrain and terminate individual plateau potentials. The results suggest that membrane depolarization produced by oscillations may activate other intrinsic conductances which generate plateau potentials, thereby providing the neuron with enhanced voltage sensitivity, compared to that produced by NMDA receptor activation alone. These oscillatory events may have a role in the regulation of motor output in a variety of rhythmic behaviours including locomotion.

Effects of inhibitory amino acid antagonists on reciprocal inhibitory interactions during rhythmic motor activity in the in vitro neonatal rat spinal cord.

1. The role of inhibitory amino acid transmission in the coordination and generation of rhythmic motor activity was examined with the use of an in vitro neonatal rat spinal cord preparation. Before adding gamma-aminobutyric acid (GABA) or glycine receptor agonists and antagonists, rhythmic motor activity was induced by bath application of acetylcholine (ACh), N-methyl-D,L-aspartate (NMA), or serotonin (5-HT) while monitoring bilateral ankle flexor and extensor electroneurograms (ENGs). The timing of rhythmic flexor and extensor discharge was consistent with that seen during overground locomotion in 27% of 84 bath applications of these substances (n = 65 preparations). 2. Subsequent addition of the GABAA receptor agonist muscimol, the GABAB receptor agonist baclofen, or glycine, abolished rhythmic activity in 95% of the tested applications. 3. GABAB receptor blockade did not disrupt alternating patterns of ENG discharge. However, addition of the GABAA receptor antagonist bicuculline, or the glycine receptor antagonist strychnine, transformed alternating flexor-extensor and left-right activity into patterns characterized by bilaterally synchronous rhythmic activation of all hindlimb ENGs. The onset of individual ENG bursts was more abrupt following bicuculline or strychnine. Strychnine also synchronized high-frequency (4-8 Hz) packets of rhythmic discharge within ENG bursts. 4. Some preparations developed synchronous, but unstable, rhythmic activity in the presence of bicuculline or strychnine alone. However, NMA, 5-HT, or ACh was usually required in addition to these antagonists to promote sustained rhythmic activity.(ABSTRACT TRUNCATED AT 250 WORDS)