Clinical relevance of reports on early access programs for checkpoint inhibitors in cancer patients: a French retrospective nationwide cohort study.

BACKGROUND: To accelerate access to new drugs, France operated an early access program known as Temporary Authorizations for Use (ATUs) until 2021. We analyzed clinical reports submitted under ATUs for immune checkpoint inhibitors (ICIs) and assessed their clinical relevance regarding the approval of ICIs in oncology. METHODS: We included all ICIs granted an ATU by the French drug safety agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM; French National Agency for the Safety of Medicines and Health Products), for patients with cancer between 1 January 2010 and 31 December 2020. We collected patients' clinical and pharmacovigilance data from ATU reports submitted by pharmaceutical companies and compared these data with those from corresponding pivotal clinical trials (CTs). RESULTS: The ATUs provided early access to 5807 patients with seven ICIs across 11 cancer indications, 1 of which had no corresponding ATU report. Of the 10 available ATU reports, only 1 included all required data. Clinical follow-up forms were available for 40.5% of patients. Differences in data reporting prevented us from comparing serious adverse events between the CTs and ATU reports. Clinicians and pharmaceutical companies often disagreed on whether ICIs caused 163 permanent treatment discontinuations, with Cohen's bias- and prevalence-adjusted κ = 0.52, 95% CI 0.33-0.68. Although agreement was almost perfect for 93 nonprogressive tumor deaths (κ = 0.88, 95% CI 0.66-0.97), 29% of ATU patient deaths remained unexplained and were reported as unrelated to treatment by the pharmaceutical companies. CONCLUSION: French ATUs facilitated early access to new ICIs for many patients with cancer. However, data attrition hindered effective real-world monitoring.

[Targeted agents in the treatment of lung cancer]. / Place des traitements ciblés dans la prise en charge des cancers broncho-pulmonaires.

Lung cancer is in France, the leading cause of cancer death. Despite the dramatic advances that have allowed in a few years to go, for metastatic cancer, from a median survival without specific treatment of 4.5 months and now almost always more than one year, survival remains disappointing and further improvements are needed. Progress in the accumulated knowledge of the inner workings of normal and tumoral cells have paved the way for the development of targeted therapeutics called biological or simply targeted therapies. Two biological processes are already the target of marketed drugs, this is the way the receptor of epidermal growth factor (EGFR) and the path of neo-angiogenesis. It is almost assumed that, in the very near future, the inhibition of EML4-ALK will also be the subject of new drugs. In the medium term, it is conceivable that the molecular dissection of the tumors actually lead to the prescription of treatments tailored to mutations and other abnormalities that direct the growth of cancers.

Subducting serpentinites release reduced, not oxidized, aqueous fluids.

The observation that primitive arc magmas are more oxidized than mid-ocean-ridge basalts has led to the paradigm that slab-derived fluids carry SO2 and CO2 that metasomatize and oxidize the sub-arc mantle wedge. We combine petrography and thermodynamic modelling to quantify the oxygen fugacity (fO2) and speciation of the fluids generated by serpentinite dehydration during subduction. Silicate-magnetite assemblages maintain fO2 conditions similar to the quartz-fayalite-magnetite (QFM) buffer at fore-arc conditions. Sulphides are stable under such conditions and aqueous fluids contain minor S. At sub-arc depth, dehydration occurs under more reducing conditions producing aqueous fluids carrying H2S. This finding brings into question current models in which serpentinite-derived fluids are the cause of oxidized arc magmatism and has major implications for the global volatile cycle, as well as for redox processes controlling subduction zone geodynamics.

Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience.

PURPOSE: Non-epithelial ovarian cancers (NEOCs) are rare diseases. Despite their overall good prognosis, the best management and current prognostic factors remain unclear. The objective of our study was to assess the clinical and pathological features of NEOC patients treated in our institution in the last 15 years and to explore risk factors for relapse and survival. METHODS/PATIENTS: All patients with a pathological diagnosis of NEOC referred to the medical oncology department at Hospital Universitario Virgen del Rocio between 1999 and 2014 were included. Demographics, tumor characteristics, treatment procedures, and clinical follow-up were retrospectively collected. Risk factors for disease-free survival (DFS) and overall survival (OS) were assessed. RESULTS: Fifty-seven patients were included, 33 (58 %) had a sex cord-stromal tumor (SCST) and 24 (42 %) had a germ-cell tumor (GCT). Median age, non-conservative surgery rates and DFS were lower in the GCT cohort; however, salvage chemotherapy led to a high proportion of complete responses in this group translating into a 90 % 3-year OS rate in both NEOC subtypes. The only identified risk factors statistically significant were stage and tumour relapse that associated, respectively, with DFS (HR = 8.84; 95 % CI 1.85-42) and OS (HR = 11.02; 95 % CI 1.76-68.7). CONCLUSIONS: Despite their rarity, NEOCs remain a highly curable group of neoplasm. In our series, a more conservative treatment approach in ovarian GCTs revealed comparable OS outcomes to SCST. No new risk factors that would help in patient stratification were identified.

Role of genotype in the adaptation of the brain dopamine system to stress.

Behavioral and biochemical analysis of the effects of stress on brain dopamine (DA) functioning in two inbred strains of mice reveals opposite patterns of adaptation to chronic stress. Chronically stressed mice of the C57BL/6 (C57) strain are characterized by hypersensitive mesolimbic DA autoreceptors and by a dramatic increase of D1/D2 DA receptor ratio (possibly postsynaptic) in the nucleus accumbens septi (NAS) as revealed by in vivo binding of 3H-spiperone and 3H-SCH23390. Chronically stressed DBA/2 (DBA) mice present, on the contrary, hyposensitive DA autoreceptors and no changes in the D1/D2 DA receptors ratio in this brain area. The analysis of the behavioral responses of chronically stressed mice of the C57 strain to the mixed D1/D2 receptor agonist apomorphine, to the selective D2 agonist LY171555 and to the selective D1 agonist SKF 38393 suggest a close relationship between the behavioral alterations produced by chronic stress and the alterations of sensitivity of D2 pre- and postsynaptic receptors in the mesolimbic system. Furthermore, chronically stressed C57 mice present a marked decrease of spontaneous-climbing behavior which is not observed in the mice of the DBA strain and is dependent on the alteration of the biphasic evolution of this behavior during exposure to the test situation which, for these mice, represents a novel environment. Acute exposure to aversive environmental conditions induces a biphasic alteration of DA transmission (initial increase of DA release followed by a decrease under control levels) in the NAS.(ABSTRACT TRUNCATED AT 250 WORDS)

Genotypic differences in central neurotransmitter responses to aging in mice.

Dopamine, serotonin, cholinergic and somatostatin responses to aging have been followed in striatum and hippocampus of two inbred strains of mice (C57BL and BALB/c). A striking strain dependency is noted. Dopaminergic mechanisms in BALB/c mice become particularly defective in striatum where both dopamine release and dopamine turnover are affected. Also, striatal cholinergic activity and somatostatin levels are more disturbed in BALB/c than in C57BL mice. For cholinergic neurotransmission and somatostatin levels, similar results are noted in hippocampus. Conversely, C57BL mice react to aging by increased serotonin turnover in hippocampus and decreased 5HIAA levels in both structures studied, whereas the BALB/c strain remains unaffected. Also, structure dependency is observed: in C57BL mice serotonin turnover appears to be unchanged in striatum and increased in hippocampus; in the BALB/c the slowing down of dopamine activity in striatum is not observed in hippocampus. This unequal capacity of central neurotransmitters and neuromodulators to adapt to aging processes, depending upon the genotype, the nervous structure and the neurotransmitter considered may be involved in man in specific pathologies in aged individuals.

In vivo biotinylated recombinant antibodies: high efficiency of labelling and application to the cloning of active anti-human IgG1 Fab fragments.

In vivo biotinylation of antibody fragments with a gene fusion approach is a realistic alternative to conventional in vitro chemical labelling. We have previously reported the construction of a vector system suitable for the bacterial expression of the binding fragment of antibody (Fab) genetically linked to the C-terminal domain of Escherichia Coli biotin carboxy carrier protein (BCCP*). A minor fraction of the expressed hybrids was biotinylated in vivo and therefore able to interact with streptavidin. We now show that the large majority of bacterially-expressed Fab-BCCP* fusions are labelled with biotin when plasmid-encoded biotin holoenzyme synthetase (BirA) is co-expressed. The yield of biotinylated Fab is maximal when overexpression of BirA is driven by a second compatible plasmid. We took advantage of this property to develop a novel filter assay for the rapid identification of recombinant Fab reacting with immunoglobulin. Starting with total RNA of two newly established murine hybridoma cell lines producing anti-human IgG1 antibodies, we selected in a single experiment the bacterial clones that expressed in vivo biotinylated anti-IgG1 Fab. Sequence analysis of the isolated Fabs showed that they did not derive from a single B clone. In addition, we found that these recombinant Fabs labelled with biotin in vivo are useful for the specific detection of human IgG1 by a solid-phase immunoassay.

Opposite effects of ibotenic acid and 6-hydroxydopamine lesions of the lateral hypothalamus on intracranial self-stimulation and stimulation-induced locomotion.

The purpose of the present study was to test the respective roles of the intrinsic neurons and of the catecholaminergic fibers in two behaviors elicited by electrical stimulation of the lateral hypothalamus, intracranial self-stimulation and the increase in locomotor activity produced by noncontingent stimulation. One group of rats was unilaterally injected in the middle lateral hypothalamus with a dose of ibotenic acid known to significantly decrease self-stimulation (4 micrograms/0.5 microliter). Two other groups received, in the same area, an injection of a small dose of 6-hydroxydopamine (2 micrograms/0.5 microliter). The rats of one of these groups were pre-treated with desmethylimipramine. Two other groups of rats were respectively injected with the vehicle of each neurotoxin. Eight days later all rats were bilaterally implanted with stimulation electrodes, one in the lesioned area, the other in the contralateral region. Each electrode of each animal was tested first for self-stimulation, then for locomotor activation measured in the open field produced by non-contingent stimulation. Whatever the lesion or the behavior tested, the response of the lateral hypothalamus contralateral to the lesioned area was normal. Self-stimulation was disturbed only with stimulation of the lateral hypothalamus lesioned by ibotenic acid. Self-stimulation in the lateral hypothalamus lesioned by 6-hydroxydopamine was normal. However, a significant loss of noradrenaline in the hippocampus and of dopamine in the striatum was observed. Furthermore, the brains of two rats unilaterally injected with the usual dose of 6-hydroxydopamine were processed for tyrosine hydroxylase immunocytochemistry.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of the nigral output pathways in the inhibitory control of the substantia nigra over generalized non-convulsive seizures in the rat.

Activation of GABAergic transmission within the substantia nigra has been shown to suppress several forms of generalized seizures in experimental models of epilepsy. More especially, such pharmacological manipulations suppress spontaneous and chemically-induced generalized non-convulsive seizures in the rat. The aim of the present study was to examine the role of the dopaminergic and GABAergic thalamic and collicular nigral outputs in this antiepileptic effect. For this purpose, we examined the effects of output destruction on the antiepileptic effect of intranigral injections of a GABA agonist or pharmacological blockade of the neurotransmission at the nerve terminal level in rats with spontaneous absence seizures. After selective destruction of dopaminergic neurons within the substantia nigra with 6-hydroxydopamine (5 micrograms/side) or hemisection of the ascending nigral output, bilateral intranigral injection of muscimol (2 ng/side) still significantly suppressed generalized non-convulsive seizures. Bilateral lesioning of the ventromedial nucleus of the thalamus did not abolish the antiepileptic effects of intranigral muscimol (2 ng/side) and the GABA antagonist, picrotoxin, when given into this thalamic nucleus (10 ng/side) also failed to induce suppression of spike and wave discharges. The antiepileptic effects of intranigral injection of muscimol (2 ng/side) was reversed by bilateral electrolytic lesions of the superior colliculus. Blockade of the GABAergic transmission at this level with picrotoxin (40 ng/side) significantly suppressed generalized non-convulsive seizures. Finally, excitation of collicular cell bodies with low doses of kainic acid (4 and 8 ng/side) also resulted in a suppression of spike and wave discharges. These results demonstrate that the GABAergic nigrocollicular pathway is critical for the inhibitory control of the substantia nigra over generalized non-convulsive seizures. The data further suggest that antiepileptic effects observed following potentiation of GABAergic transmission in the substantia nigra result from a disinhibition of collicular cell bodies.

Facilitation of learning consecutive to electrical stimulation of the locus coeruleus: cognitive alteration or stress-reduction?

This chapter summarizes behavioral and neurochemical data on the delayed effect of locus coeruleus stimulation on learning capabilities in the rat. The initial observation showed that electrical stimulation of the locus coeruleus of a 15-day-old-rat improved the early stages of acquisition and extinction of a food-reinforced task performed 4 weeks later. Neurochemical lesion of the dorsal noradrenergic bundle performed 10 days before the stimulation did not attenuate the behavioral effect, whereas the lesion of the locus coeruleus proper suppressed the subsequent behavioral improvement. More recently we showed that the increase of adrenocorticotrophin release consecutive to a moderate stressful situation was significantly lower in previously stimulated rats than in implanted non-stimulated animals. Furthermore, we demonstrated that the neurochemical lesion of the locus coeruleus increased neophobia in the open-field as well as in a specific exploration task. Taken together these data strongly suggest that the long-term improvement in acquisition and extinction of locus coeruleus-stimulated rats results mainly from an attenuated stress reaction when these animals are confronted with a new environment (beginning of acquisition) or a new situation (beginning of extinction). Finally, we were interested in investigating the possibility of some long-term neurochemical modifications that could be related to the observed behavioral effects. The most significant modification observed concerned certain subpopulations of adrenoceptors in specific brain regions. By using specific ligands of the beta-, alpha 1- and alpha 2-adrenoceptors, we studied the long-term effect (4 weeks) of the locus coeruleus stimulation on the kinetic characteristics of these three sub-types of receptors in four brain areas (the cortex, hippocampus, hypothalamus and brainstem). No significant alteration in the density of beta binding sites was observed in any of the four structures analyzed; likewise locus coeruleus stimulation did not modify the density or affinity of the beta-, alpha 1- and alpha 2-receptors in the brainstem. The density of alpha 1- and alpha 2-receptors was significantly increased in the cortex whereas in the hippocampus only the density of the alpha 2-receptors was increased. Finally, a very large increase of the density of alpha 2-adrenoceptors was observed in the hypothalamus (113%). In each case the increase in receptor density was also associated with a decreased affinity. A behavioral counterpart of these changes in the kinetic properties of the alpha 2-receptors has been observed by using a pharmacological approach.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat striatum.

Dopamine D2 receptor gene expression was examined in rat striatum after chronic treatment with N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine at 15 mg/kg/day or MK-801 at 0.1, 0.2 and 0.4 mg/kg/day per os, for 50 days). The long-isoform mRNA, as well as the total D2 mRNA expression were induced. No change was noticed in striatal dopamine release or turnover. D2 binding studies carried out in MK-801 chronically treated (0.3 mg/kg/day per os, for 50 days) and control rats revealed an increased receptor density in treated animals without a significant change in receptor affinity. These results suggest that the synthesis of both striatal D2 receptor isoforms is postsynaptically regulated at the transcriptional level, by events triggered by glutamate through the NMDA-type receptor.

Effect of hypothalamic injections of 5,7-dihydroxytryptamine on elicitation of mouse-killing in rats.

An overall and marked serotonin (5-HT) depletion of the brain was found to facilitate initiation of mouse-killing behavior in the rat, whereas more selective 5-HT depletions within forebrain structures such as the septum, hippocampus, cingular cortex and amygdala, did not have such an effect. In order to further investigate the topography of the 5-HT pathways and terminals though to be involved in an inhibitory control over this behavior, localized lesions of the serotonergic system(s) were performed by means of bilateral 5,7-dihydroxytryptamine (5,7-DHT) injections (5 microgram/microliter) into the hypothalamus in naive rats. 5,7-DHT injections into the medial hypothalamus did not affect the initiation of mouse-killing behavior, whereas the reflexive startle responses to air puffs were increased. The animals' open-field behavior remained unchanged. Forebrain 5-HT content was reduced by 50% in this group. 5,7-DHT injections into the lateral hypothalamus increased the proportion of killers to 46% as compared to 10% in the control group, in spite of a reduced activity in the open-field and unchanged startle responses. Forebrain 5-HT content was reduced by 88%. As the lateral hypothalamus contains afferents from both the dorsal and the median raphe nuclei, it is likely that 5-HT terminals modulate some hypothalamic mechanism involved in the control of mouse-killing behavior.

Selective increase of offensive behavior in the rat following intrahypothalamic 5,7-DHT-induced serotonin depletion.

Cerebral serotonin (5-HT) depletions usually increase aggressive behaviors and more specifically facilitate elicitation of offensive behaviors. In order to localize the brain structures involved in this effect, 5,7-dihydroxytryptamine (5,7-DHT), a neurotoxin of 5-HT neurons, was injected into the ascending serotonergic pathway within the lateral hypothalamus, thus depleting 5-HT only in the forebrain structures. The effects of such treatment on offensive and defensive as well as social and non-social behaviors were studied in resident rats confronted with untreated intruders. Pretreatment with desipramine protected noradrenergic neurons. The content of 5-HT fell to 25% of controls, whereas noradrenaline was maintained at 90% in the forebrain anterior to the injection site. Ethological analysis of both resident's and intruder's behavior showed that offensive items were increased in 5,7-DHT-treated residents, whereas defensive items were increased in their non-treated partners; non-social activities were unchanged. Control of mouse-killing behavior during a 2-h test in the same animals showed a clear increase in elicitation of killing in 5,7-DHT-injected rats. These results confirm that the inhibitory control of serotonin is exerted specifically on offensive aggression. They suggest that forebrain structures are involved in this control.

Enhancement of learning four weeks after stimulation of the nucleus locus coeruleus in the rat: differential effects of dorsal noradrenergic bundle lesion and lesion of the locus coeruleus proper.

In previous studies we showed that electrical stimulation of the nucleus locus coeruleus produced, four weeks later, a significant improvement in performance in acquisition of food-reinforced operant conditioning. In the two experiments reported here, we tested the role of the dorsal noradrenergic bundle and of the locus coeruleus proper in this long-term effect. Lesioning the dorsal noradrenergic bundle did not have a clear and consistent effect, whereas lesion of the nucleus coeruleus proper suppressed almost totally the beneficial effect of the stimulation. In the first experiment, the dorsal noradrenergic bundle was lesioned by local bilateral injection of 6-hydroxydopamine, 8 days before stimulation of the locus coeruleus. Four weeks after the stimulation, the rats were tested for acquisition of the operant task. Three control groups were used: not lesioned but stimulated, lesioned but not stimulated, and not lesioned/not stimulated. The locus coeruleus stimulation produced the same improvement of performance at the beginning of the acquisition, whether or not the dorsal noradrenergic bundle had been lesioned. However, a significant decrement of performance was observed in lesioned and stimulated rats during the last 40 min of the acquisition. In the second experiment, the locus coeruleus proper was destroyed by bilateral local injection of 6-hydroxydopamine and the locus coeruleus region was stimulated 15 days later. Three control groups were used, as in the first experiment. All the rats were tested 4 weeks later for acquisition of the operant task. The locus coeruleus lesion significantly attenuated the beneficial effect of the stimulation; however, the performance of the lesioned and stimulated rats was still significantly superior to that of the lesioned but not stimulated rats. These results suggest that the noradrenergic locus coeruleus system is involved in the long-term effect, but that the rostral projections passing through the dorsal bundle, in front of the lesion, are not critically involved in the observed effect.

Circadian variations of noradrenaline, 5-hydroxytryptamine and dopamine in specific brain areas of C57Bl/6 and BALB/c mice.

Daily variations in noradrenaline, 5-hydroxytryptamine and dopamine turnover were evident in two strains of mice (C57Bl/6 and BALB/c) subjected to 12-12 h light-dark cycles. These fluctuations were also evident under continuous light (L-L) in C57Bl/6 mice only, a strain which is characterized by clear-cut circadian wheel running activity in the absence of external synchronizers.

Dopamine and melatonin interactions in the intact chicken eye. Electrooculographic and biochemical study.

Electrophysiological and biochemical techniques were used to investigate the interactions between dopamine (DA) and melatonin (MEL) in the intact chicken eye. Endogenous DA depletion induced by intraocular administration of alpha-methyl-para-tyrosine (alpha-MPT), a selective tyrosine hydroxylase inhibitor, decreases the transepithelial potential (TEP) of the retinal pigment epithelium and reduces the light peak (LP) recorded by an indirect electro-oculographic (EOG) method. An intraocular injection of MEL also reduces the TEP but does not reduce the LP. Retinal MEL is increased after endogenous DA depletion and a tight inverse correlation between DA and MEL contents was found. The present data, together with other findings support the hypothesis (1) that in the intact chicken eye, DA and MEL play respectively a role of light and dark signals on the TEP, and (2) that a balance between these two neurohormones may be responsible for the regulation of RPE events which are dependent on light-dark conditions.

Facilitation of spontaneous and learned spatial behaviours following 6-hydroxydopamine lesions of the lateral septum: a cholinergic hypothesis.

Mice received injections of 6-hydroxydopamine (6-OHDA) in the lateral septum; they were tested for spontaneous alternation, acquisition and reversal of a spatial discrimination in a T-maze. In each of these tasks, performance of 6-OHDA lesioned mice was improved relative to controls. Neurochemical analysis revealed that 6-OHDA lesioned mice exhibited a significant increase in the rate of sodium-dependent high affinity choline uptake in the hippocampus. These results are discussed in relation to current theories concerning the role of the septo-hippocampal complex and cholinergic system in the control of behaviour.

Intrinsic neurons are involved in lateral hypothalamic self-stimulation.

The recent technique of using ibotenic acid to lesion selectively local neurons while sparing fibers of passage permitted us to answer a long-standing question: is lateral hypothalamic self-stimulation supported by fibers of passage or are the intrinsic hypothalamic neurons involved? Three groups of adult male Sprague-Dawley rats were used. In a normal group, electrodes were bilaterally implanted in the lateral hypothalamus and self-stimulation (ICSS) was obtained separately with the right and left electrodes, at various current intensities, using a nose-poke response. In the experimental group, the intrinsic neurons of the lateral hypothalamus were destroyed unilaterally by local injection of ibotenic acid (4 or 6 micrograms in 0.5 microliter); the other side served as the sham-lesion control. Ten days later ICSS electrodes were implanted bilaterally, one in the lesioned area, the other in the contralateral hypothalamus. As in the case of the normal animals, the rate of nose-poking (ICSS) was then determined separately for each electrode. In the normal rats, ICSS rates were the same with stimulation on either side and the increase in ICSS rate as a function of the increase in current intensity was the same on each side. In the experimental rats, ICSS of the lesioned side was decreased in all cases; moreover, after lesion with the 6 micrograms dose, ICSS was totally suppressed. Self-stimulation of the sham-lesioned side was not significantly different from that observed in the normal rats. In 6 rats sampled from the lesioned groups as well as in 3 additional unimplanted animals, biochemical assays compared dopamine and serotonin contents of the two striata and noradrenaline and serotonin contents of the two hippocampi. No difference was observed for these two structures between the side ipsilateral to the lesion and the contralateral side. Moreover, none of these monoamine levels differed from those seen in the unimplanted rats. These results, taken together, suggest that intrinsic lateral hypothalamic neurons are involved in ICSS.

Effects of immobilization stress on dopamine and its metabolites in different brain areas of the mouse: role of genotype and stress duration.

Immobilization stress induced, in mice of both C57BL/6 (C57) and DBA/2 (DBA) strains, an increase in dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios and a reduction of 3-methoxytyramine (3-MT)/DA ratio in the caudatus putamen (CP) and nucleus accumbens septi (NAS). These effects were already evident after 30 min stress in the NAS, while in the CP 120 min were needed in order to show the effects of stress. Immobilization did not produce any effects on dopaminergic metabolism in the frontal cortex (FC) of the C57 strain either after 30 or after 120 min stress while in mice of the DBA strain a time-dependent effect of stress on the HVA/DA ratio was evident. When B6D2F1 hybrids were considered, the effects produced by 120 min immobilization in the CP and the NAS paralleled those observed in parental strains, while in the FC 120 min stress induced the same increase of HVA observed in DBA mice, thus suggesting that the pattern of response in the FC that characterizes the DBA strain may be inherited through a dominant pattern of inheritance.