Immune checkpoint inhibitors-related encephalitis in melanoma and non-melanoma cancer patients: a single center experience.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICI) has greatly improved survival for patients with a number of malignant diseases in recent years. Neurological immune-related adverse events (n-irAE) of varying severity have been reported in the literature. We aimed to identify the incidence of n-irAE, focusing on immune-related encephalitis (IRE), in patients treated with ICI for multiple non-hematological malignancies in our institution. METHODS: All patients with histologically verified cancer that received treatment with ICI at the Sheba Medical Center between January 2017 and August 2019 were surveyed. Medical records for each patient were reviewed and information regarding n-irAE was recorded. RESULTS: In total, 1993 patients were included. Eleven cases of IRE were recorded, affecting 0.55% of patients overall, eight had non-melanoma cancer. Eight patients had made a full recovery. CONCLUSIONS: IRE is a n-irAE more frequent than previously reported, particularly in non-melanoma patients. The diagnostic criteria and optimal treatment needs to be determined. ICI re-challenge after IRE can be considered for selected patients.

Hyperproinsulinemia in the diabetic Psammomys obesus is a result of increased secretory demand on the beta-cell.

We have recently shown that the diabetic syndrome in Psammomys obesus is characterized by severe depletion of islet immunoreactive insulin (IRI) stores together with a marked increase in the islet proinsulin to insulin ratio. In the present in vitro studies, we show marked enhancement of proinsulin biosynthesis in islets from diabetic P. obesus (approximately 8-fold compared to nondiabetic islets). Proinsulin to insulin conversion and insulin degradation do not differ significantly between diabetic and nondiabetic islets. The rate of IRI secretion at a stimulatory concentration of glucose (16.7 mM) is comparable in diabetic and nondiabetic animals, but at a nonstimulatory glucose concentration (0 mM), islets obtained from diabetic animals show significant IRI release. beta-Cells from diabetic P. obesus also exhibited increased secretion of newly synthesized proinsulin and conversion intermediates under stimulatory conditions. Moreover, a novel secretory compartment, highly enriched in newly synthesized C peptide, characterized the beta-cells of diabetic animals. Our data suggest that the marked insulin depletion observed in diabetic islets is probably due to a hyperglycemia-driven increase in secretory demand that is not met by the enhanced biosynthetic capacity of these islets. This leads to relative enrichment of the depleted diabetic islets with immature secretory granules of a higher proinsulin content.

Insulin secretion in obese and non-obese NIDDM.

Both the insulin response to glucose and the sensitivity to insulin show large variation in the normal population. Many subjects have either a markedly low insulin response or low sensitivity to insulin, with nevertheless normal glucose tolerance. For such subjects to become diabetic, insulin secretion or insulin action must further deteriorate with time, or other factors are added which tip the balance towards diabetes. Most evidence to date indicates that reduced beta-cell responsiveness and reduced insulin sensitivity co-exist in subjects prior to developing NIDDM. Both insulin secretion and insulin action are genetically controlled and influenced by intrauterine and neonatal factors. Insulin secretion and insulin action vary inversely in a closely linked manner; inability to fully compensate for changes in one variable may generate a functional deficit in glucose homeostasis. Subjects combining low functions would run a proportionately larger risk of decompensating the glucose tolerance and be more vulnerable, in terms of diabetes susceptibility, to factors that further reduce insulin output or insulin action. Careful analysis of existing data prompts us to ascribe a dominating role to the impairment of insulin secretion in the pathogenesis of IGT and NIDDM. Patients with NIDDM also exhibit increased proportions of proinsulin and proinsulin conversion intermediates. We used hyperinsulinaemic diabetic and non-diabetic Psammomys obesus to study the possible relationship between steady-state pancreatic insulin stores and the proportion of proinsulin-related peptides in the plasma and the pancreas. A marked increase in these peptides was associated with 90% reduction in insulin stores of the pancreas. After food deprivation, the depletion of pancreatic insulin in the diabetic animals was partially corrected, and the proinsulin/insulin ratio normalized. In contrast, non-diabetic psammomys showed only 50% reduction in pancreatic insulin stores under non-fasting conditions, with no change in proinsulin/insulin ratio. These findings suggest that in the diabetic Psammomys obesus, pancreatic capacity for storage/production of insulin is limited; the metabolic consequences of this limitation are amplified by increased secretory demand secondary to insulin resistance, thus facilitating the establishment of hyperglycaemia, which may in itself further exacerbate the pancreatic dysfunction.

Hyperproinsulinemia and insulin deficiency in the diabetic Psammomys obesus.

Patients with noninsulin-dependent diabetes mellitus exhibit increased proportions of plasma proinsulin and proinsulin conversion intermediates. We used hyperinsulinemic diabetic and nondiabetic Psammomys obesus to study the possible relationship between steady state pancreatic insulin stores and the proportion of proinsulin-related peptides in the plasma and pancreas. Insulin-like peptides were separated by reverse phase HPLC and identified by pulse-chase experiments. A marked increase in the proportions of proinsulin and proinsulin conversion intermediates in the plasma and pancreas of diabetic nonfasted Psammomys was associated with 90% reduction in insulin stores of the pancreas. After a 16- to 20-h fast, the depletion of pancreatic insulin in the diabetic animals was partially corrected, and the proinsulin/insulin ratio was normalized. In contrast, nondiabetic Psammomys showed only 50% reduction in pancreatic insulin stores under nonfasting conditions, with no change in the proinsulin/insulin ratio. These findings suggest that in the diabetic Psammomys obesus, the pancreatic capacity for storage of insulin may be limited; the metabolic consequences of this limitation are amplified by increased secretory demand secondary to insulin resistance, thus facilitating the establishment of hyperglycemia, which may in itself further exacerbate pancreatic dysfunction.

Functional analysis of a CArG-like promoter element in cardiac myosin light chain 2 gene.

We have examined the functional properties of a putative regulatory sequence, CCAAAAGTGG, (element A) in chicken cardiac myosin light chain 2 (MLC2) gene promoter by deletion/substitution mutagenesis and transcriptional analysis of RNA by S1 nuclease mapping. The results indicate that the element A sequence, which resembles the evolutionarily conserved A/T-rich CArG box, plays a role in defining the transcription initiation site in MLC2 gene. This is accomplished via repression of a potential transcription initiation at site -40 and promoting the initiation at +1. One of the two other dA-dT-rich sequences (element C), located proximal to initiation site (+1), serves as the basal promoter while the distal A/T rich element B participates in tissue specific transcription of the gene.

Cyclic juvenile hormone biosynthesis in the cockroach, Blattella germanica: effects of ovariectomy and corpus allatum denervation.

The corpora allata (CA) of ovariectomized adult Blattella germanica females exhibited delayed but high rates of juvenile hormone biosynthesis in vitro. Using the onset of sexual receptivity as a probe of the degree of CA activation in females, we demonstrated at least one cycle of CA activity in the experimentally synchronized ovariectomized females. Following their activation, the CA exhibited a partial and transient decline in activity, but in contrast to the CA of intact females, this decline was not accompanied by a regression in CA volume. CA of intact and ovariectomized females that were denervated from the brain were activated, but the subsequent decline in CA activity at the end of the cycle was prevented in ovariectomized females. The presence of an egg-case suppressed the reactivation of the inactive CA in intact females but not in CA-denervated females. We conclude that activation of the CA in B. germanica is not dependent upon either the presence of the ovary or intact nervous connections between the CA and the brain. The brain exerts a partial inhibition on CA activity through intact nerves which is relieved (by disinhibition) in the presence of a young ovary but is enhanced and sustained in the presence of the egg-case. Inhibition of the CA also occurs independently of nervous connections with the brain through factors that originate in the mature ovary and affect both CA activity and morphology.

Developmental regulation of juvenile hormone synthesis: ovarian synchronization of volumetric changes of corpus allatum cells in cockroaches.

The corpus allatum (CA) cells of adult Blattella germanica females undergo cyclic volumetric changes in relation to juvenile hormone (JH) synthesis. In intact females the size of CA cells changes synchronously during the gonotrophic cycle, resulting in cyclic JH synthesis. In ovariectomized females volumetric changes among CA cells become asynchronous, resulting in highly variable but high rates of JH synthesis. Injection of the steroid hormone 20-hydroxyecdysone into ovariectomized females with active CA resulted in a transient decline followed by an increase in both CA volume and JH biosynthesis. This response was due to a change in the size distribution of CA cells and not in the total number of CA cells. In ovariectomized females, CA cells can be re-synchronized into a uniform population of small inactive cells with injection of 20-hydroxyecdysone and implantation of an artificial egg-case, mimicking the successive events of ovulation, oviposition and pregnancy.

Sexual differentiation of nymphal corpora allata and the effects of ovariectomy on adult gland morphometrics in Blattella germanica.

Changes in the number of corpus allatum (CA) cells were investigated in nymphs and in intact and ovariectomized adult female Blattella germanica. The CA of intact adult females exhibit cyclic changes in volume in relation to juvenile hormone (JH) synthesis, while the CA of ovariectomized females become significantly hypertrophied as a result of a gradual and continuous increase in volume that is independent of JH biosynthesis. In both intact and ovariectomized females changes in JH synthesis and CA volume are not related to total cell number which remains relatively constant. However, adult females have twice as many CA cells as do adult males as a result of a female-specific increase in total cell number late in the last nymphal instar.

Morphometric analysis of corpus allatum cells in adult females of three cockroach species.

The number of cells and their sizes in the corpus allatum (CA) of adult female Blattella germanica, Supella longipalpa and Diploptera punctata were determined during oocyte maturation. Cell number and size were directly measured in cell suspensions following enzymatic dissociation of freshly excised CA. Cell numbers were verified by total cell counts in whole-mount CA monolayers and by hemocytometric sampling. In all three species, cell number did not change during the period of CA activation, averaging ca. 2000 cells per gland in B. germanica, 3500 cells per gland in S. longipalpa and 11,000 cells per gland in D. punctata. Cell diameter increased significantly in all three species during this period from a mean value of 8.9 microns to 11.7 microns in B. germanica, from 9.2 microns to 14.6 microns in S. longipalpa and from 10.0 microns to 15.6 microns in D. punctata. During a 4 h incubation period, dissociated CA cells incorporated L-[methyl-3H]-methionine into juvenile hormone-III at rates comparable to intact glands. These data suggest that CA activation in the first ovarian cycle of these species is associated mainly with an increase in cell size with minor changes in cell number.

The intrinsic synthesis of juvenile hormone-III diol by locust corpora allata in vitro.

Juvenile hormone (JH)-III 10-11-diol is intrinsically synthesized and released from the corpora allata (CA) of adult locust females in vitro, together with JH-III. JH-III synthesis is preferentially stimulated and diol production only slightly enhanced, by cerebral locust allatotropin. The identification of JH-III diol is based on: similar ratio of incorporation of 14C/3H from radiolabelled [2-14C]acetate and [methyl-3H]methionine, to that of JH-III; similar chromatographic properties to those of synthetic diol on an RP-18 column eluted with acetonitrile, and similar chromatographic properties of acetylated derivatives; mass spectrometric analysis of derivatives and fragmentation products. Exogenous radiolabelled JH-III is not degraded during incubation with locust CA in vitro, corroborating the endogenous production of JH-III diol. Allatal diol formation may be an additional mechanism for the control of JH-III levels in locusts, preceding release into the hemolymph.

Farnesoic acid and allatotropin stimulation in relation to locust allatal maturation.

Allatal maturation during the first gonotrophic cycle of adult female Locusta migratoria can be measured in vitro by the competence of these glands to produce juvenile hormone III (JH-III) when maximally stimulated by either farnesoic acid (FA) or allatotropin. Maturation precedes the full activation of the corpora allata (CA) during the first cycle of oogenesis. Basal activity of mature active female CA is highly correlated to stimulated activity. This suggests that between-gland variability reflects the inherent competence of each individual CA, and is not a consequence of a mere pulsatile on/off activation. Older glands may be inactive but their competence is equivalent to that of mature active glands. The kinetics of FA and allatotropic stimulation in vitro are equivalent, suggesting that allatotropin affects rate-limiting steps preceding FA biosynthesis.