Immune checkpoint-targeted antibodies: a room for dose and schedule optimization?

Anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors are therapeutic monoclonal antibodies that do not target cancer cells but are designed to reactivate or promote antitumor immunity. Dosing and scheduling of these biologics were established according to conventional drug development models, even though the determination of a maximum tolerated dose in the clinic could only be defined for anti-CTLA-4. Given the pharmacology of these monoclonal antibodies, their high interpatient pharmacokinetic variability, the actual clinical benefit as monotherapy that is observed only in a specific subset of patients, and the substantial cost of these treatments, a number of questions arise regarding the selected dose and the dosing interval. This review aims to outline the development of these immunotherapies and considers optimization options that could be used in clinical practice.

LiCl-induced sickness modulates spontaneous activity and response dynamics in rat gustatory cortex.

Gustatory Cortex (GC), a structure deeply involved in the making of consumption decisions, presumably performs this function by integrating information about taste, experiences, and internal states related to the animal’s health, such as illness. Here, we investigated this assertion, examining whether illness is represented in GC activity, and how this representation impacts taste responses and behavior. We recorded GC single-neuron activity and local field potentials (LFP) from healthy rats and (the same) rats made ill ( via LiCl injection). We show (consistent with the extant literature) that the onset of illness-related behaviors arises contemporaneously with alterations in spontaneous 7-12Hz LFP power at ~11 min following injection. This process was accompanied by reductions in single-neuron taste response magnitudes and discriminability, and with enhancements in palatability-relatedness – a result reflecting the collapse of responses toward a simple “good-bad” code arising in a specific subset of GC neurons. Overall, our data show that a state (illness) that profoundly reduces consumption changes basic properties of the sensory cortical response to tastes, in a manner that can easily explain illness’ impact on consumption.

Glycopyrrolate for drooling in children with medical complexity under three years of age

Background The aim of the study is to determine that Glycopirrolate is safe and effective in decreasing drooling in children with medical complexity under 3 years of age. Medical treatment is based on anticholinergic drugs as transdermal scopolamine, benzotropine and GLY. GLY (Glycopyrronium bromide) is a synthetic quaternary ammonium anticholinergic agent with poor blood–brain barrier penetration and consequently has limited central effects. Actually, the oral GLY formulation was approved by the United States Food and Drug Administration (FDA) to treat drooling in children aged 3–16 years. Five studies reported on GLY use for the treatment of drooling in children with cerebral palsy and other conditions with neurological impairment; four are prospective studies while one a retrospective review. Methods this is a case report of eighteen children (sex ratio 11/8, median age 17 months, range 2–36 months) under three years of age, followed by a multidisciplinary team at the Bambino Gesù Children Hospital. The median follow-up was of 31.5 months (range 1–69 months). Response to treatment was assessed according to the Drooling Impact Scale administered at time 0 and after 1 month. All patients have an important neurological impairment: nine patients have a cerebral palsy (Gross Motor Function Classification System class V) and nine a genetic/malformative syndrome. Twelve patients have a tracheostomy and two need mechanical ventilation. Gastrostomy is present in 16 out of 18 patients. All patients received Glycopirrolate. The median starting daily dose was 0.065 mg/kg/die (range 0.02–0.21 mg/kg/die) three times a day. The drooling impact scale was administered at time O and after 1 month. Results Four out 18 patients stopped treatment for adverse event, lack of efficacy or parental decision. The mean Drooling Impact Scale at time 0 was 89 (range 81–100) and after 1 month 61(range 43–78); the difference was statistically significant (P < 0.001). The overall response to treatment was 94%. Conclusions This is the first study to determine the safety and effectiveness of Glycopyrrolate in decreasing drooling in a specific subset of patients. No major side effects were observed. Further comparative studies are needed to confirm our results.

Instructional Design, Educational Technology, and LGBTQ Students

As diversity and social justice have become more important in education, educators are beginning to realize that their lessons, both real and virtual, need to be more inclusive. More specifically, this chapter addresses the culture, learning, and relationship with technology of a specific subset of students: individuals who identify as lesbian, gay, bisexual, transsexual/transgender, and queer/questioning (LGBTQ) or who have LGBTQ parents, guardians, friends, and/or family. Suggestions for educators on inclusive strategies when integrating technology into lessons through digital activities and various educational technology tools, as well as inclusive instructional design suggestions, are included. As for the question addressed in the title, none is the answer because all three of these things belong together in all forms of education, in all types of schools, and by all types of educators.

BRG1 defines a genomic subset of inflammatory genes transcriptionally controlled by the glucocorticoid receptor

Glucocorticoids (such as Dexamethasone) are commonly used immunomodulatory drugs with potent anti-inflammatory effects, whose mechanisms of action remain incompletely understood. They bind to the Glucocorticoid Receptor (GR), a nuclear hormone receptor that acts as a transcription factor to directly control the expression of inflammatory genes. To elucidate the complex molecular mechanisms employed by GR during the suppression of innate immune responses, we have performed proteomics, ChIP-seq, ATAC-seq, RNA-seq and bioinformatics together with genetic and pharmacological loss of function studies in primary mouse macrophages. We found that GR interacts with the ATP-dependent SWI/SNF chromatin remodeling complex to regulate a specific subset of target genes. Here we show that the central catalytic subunit BRG1 is required not only for the transcriptional activation of classical GR target genes such as Fkbp5 or Klf9, but also for the transcriptional repression of cytokines and chemokines such as Ccl2, Cxcl10 or Il1a. We demonstrate that loss of BRG1 activity leads to reduced histone deacetylase (HDAC) function, and consequently increased histone acetylation, at these repressive GR binding sites. Altogether, our findings suggest that GR interacts with BRG1 to assemble a functional co-repressor complex at a defined fraction of macrophage cis-regulatory elements. These results may indicate additional non-classical, remodeling-independent functions of the SWI/SNF complex and may have implications for the development of future immunomodulatory therapies.

RPL3L-containing ribosomes modulate mitochondrial activity in the mammalian heart

ABSTRACTThe existence of naturally occurring ribosome heterogeneity is now a well-acknowledged phenomenon. However, whether this heterogeneity leads to functionally diverse ‘specialized ribosomes’ is still a controversial topic. Here, we explore the biological function of RPL3L, a ribosomal protein (RP) paralog of RPL3 that is exclusively expressed in muscle and heart tissues, by generating a viable homozygous Rpl3l knockout mouse strain. We identify a rescue mechanism in which, upon Rpl3l depletion, RPL3 becomes upregulated, yielding RPL3-containing ribosomes instead of RPL3L-containing ribosomes that are typically found in cardiomyocytes. Using both ribosome profiling (Ribo-Seq) and a novel orthogonal approach consisting of ribosome pulldown coupled to nanopore sequencing (Nano-TRAP), we find that RPL3L neither modulated translational efficiency nor ribosome affinity towards a specific subset of transcripts. By contrast, we show that depletion of RPL3L leads to increased ribosome-mitochondria interactions in cardiomyocytes, which is accompanied by a significant increase in ATP levels, potentially as a result of mitochondrial activity fine-tuning. Our results demonstrate that the existence of tissue-specific RP paralogs does not necessarily lead to enhanced translation of specific transcripts or modulation of translational output. Instead, we reveal a complex cellular scenario in which RPL3L modulates the expression of RPL3, which in turn affects ribosomal subcellular localization and, ultimately, mitochondrial activity.

»Was sich der Wald erzählt« von Gustav zu Putlitz

Artikelbeginn:[English title and abstract below] Im Jahr 1866 veröffentlicht Theodor Storm im Verlag Gebrüder Paetel in Berlin seinen Band Drei Märchen. Dieser erfährt von seinen sonst mehr als eifrigen Rezensenten so wenig Beachtung, dass Storm am 2. Februar 1873 in einem Brief an die Verleger zur geplanten Neuauflage des Bandes klagt: »Bei der Antipathie des Publicums gegen das Wort ›Märchen‹ – die Leute wittern dann gleich wirkliche, pure Poësie, wovor sie eine unglaubliche Angst haben –, hätte das Buch einen anderen Titel haben sollen« (Berbig 2006, S. 52). Die geplante Titeländerung setzt Storm dann auch konsequent um und wiederholt die Klage über den schlechten Ruf des Märchens auch im Vorwort des von ihm programmatisch umgetauften Märchenbandes, der jetzt Geschichten aus der Tonne heißt (vgl. Conrad 2018). Gustav zu Putlitz’s What Was Said in the WoodsOn ›Precarious Literature‹ and ›Precarious Knowledge‹ in Children’s Literature around the 1850s This article focusses on the collection of fairy tales Was sich der Wald erzählt. Ein Märchenstrauß (1850) [What Was Said in the Woods (1851)] by Gustav zu Putlitz, reading it as an exemplary text for a corpus of forgotten children’s literature of the nineteenth century. Towards the end of that century, a popular ›cosmos literature‹ emerged, initially in the form of interpretations of Alexander von Humboldt’s Cosmos: A Sketch of a Physical Description of the Universe (1845 – 1862), later as prose which propagated a form of (popular) science which deviated completely from the modern understanding of science. This specific subset of noncanonised texts can be conceived as ›precarious literature,‹ based on Martin Mulsow’s concept of ›precarious knowledge.‹ This article presents the preliminary findings of a research project that aims to systematise, as ›precarious literature,‹ texts of nineteenth century children’s literature which were then highly regarded, influential and widely read but are today largely forgotten. The reason postulated is that this literature contains knowledge which was, at that time, ›precarious.‹ The research project endeavours to understand precarious literature as a noncanonical sociocultural space in which controversial fields of knowledge and their dynamics are coded, still waiting to be unlocked.

Layer-specific developmentally precise axon targeting of transient suppressed-by-contrast retinal ganglion cells (tSbC RGCs)

The mouse retina encodes diverse visual features in the spike trains of more than 40 retinal ganglion cell (RGC) types. Each RGC type innervates a specific subset of the more than 50 retinorecipient brain areas. Our catalog of RGC types and feature representations is nearing completion. Yet, we know little about where specific RGC types send their information. Furthermore, the developmental strategies by which RGC axons choose their targets and pattern their terminal arbors remain obscure. Here we identify a genetic intersection (Cck-Cre and Brn3cCKOAP) that selectively labels transient Suppressed-by-Contrast (tSbC) RGCs, a member of an evolutionarily conserved functionally mysterious RGC subclass. We find that tSbC RGCs selectively innervate the dorsolateral and ventrolateral geniculate nuclei of the thalamus (dLGN and vLGN), the superior colliculus (SC), and the nucleus of the optic tract (NOT). They binocularly innervate dLGN and vLGN but project only contralaterally to SC and NOT. In each target, tSbC RGC axons occupy a specific sublayer, suggesting that they restrict their input to specific circuits. The tSbC RGC axons span the length of the optic tract by birth and remain poised there until they simultaneously innervate their four targets around postnatal day five. The tSbC RGC axons make no errors in choosing their targets and establish mature stratification patterns from the outset. This precision is maintained in the absence of Brn3c. Our results provide the first map of SbC inputs to the brain, revealing a narrow target set, unexpected laminar organization, target-specific binocularity, and developmental precision.

Development of an Oxidative Phosphorylation-Related and Immune Microenvironment Prognostic Signature in Uterine Corpus Endometrial Carcinoma

Background: As the fourth most common malignant tumors in women, uterine corpus endometrial carcinoma (UCEC) requires novel and reliable biomarkers for prognosis prediction to improve the overall survival. Oxidative phosphorylation (OXPHOS) is found to be strongly correlated with the progression of tumor. Here, we aimed to construct an OXPHOS-related and immune microenvironment prognostic signature to stratify UCEC patients for optimization of treatment strategies.Method: Prognosis-associated OXPHOS-related differentially expressed genes were identified by multivariable Cox regression from TCGA–UCEC cohort. Based on the candidate genes, an OXPHOS-related prognostic signature was constructed by the train set data and verified by the entire set. When integrated with relevant clinical characteristics, a nomogram was also created for clinical application. Through comparison of tumor microenvironment between different risk groups, the underlying mechanism of the model and the inner correlation between immune microenvironment and energy metabolism were further investigated.Results: An OXPHOS-related signature containing ATP5IF1, COX6B1, FOXP3, and NDUFB11 was constructed and had better predictive ability compared with other recently published signatures in UCEC. Patients with lower risk score showed higher immune cell infiltration, higher ESTIMATE score (p = 2.808E−18), lower tumor purity (p = 2.808E−18), higher immunophenoscores (IPSs) (p &lt; 0.05), lower expression of mismatch repair (MMR) proteins (p &lt; 0.05), higher microsatellite instability (MSI), lower expression of markers of N6-methyladenosine (m6A) mRNA methylation regulators, higher tumor mutation burden (TMB) (p = 1.278E−9), and more sensitivity to immune checkpoint blockade (ICB) (p &lt; 0.001) and chemotherapy drugs, thus, possessing improved prognosis.Conclusion: An OXPHOS-related and immune microenvironment prognostic signature classifying EC patients into different risk subsets was constructed in our study, which could be used to predict the prognosis of patients and help to select a specific subset of patients who might benefit from immunotherapy and chemotherapy, thus, improving the overall survival rate of UCEC. These findings may contribute to the discovery of novel and robust biomarkers or target therapy in UCEC and give new insights into the molecular mechanism of tumorigenesis and progression of UCEC.

Kv1 channels regulate variations in spike patterning and temporal reliability in the avian cochlear nucleus angularis

Diverse physiological phenotypes in a neuronal population can broaden the range of computational capabilities within a brain region. The avian cochlear nucleus angularis (NA) contains a heterogeneous population of neurons whose variation in intrinsic properties results in electrophysiological phenotypes with a range of sensitivities to temporally modulated input. The low-threshold potassium conductance (GKLT) is a key feature of neurons involved in fine temporal structure coding for sound localization but a role for these channels in intensity or spectrotemporal coding has not been established. To determine whether GKLT affects the phenotypical variation and temporal properties of NA neurons, we applied dendrotoxin (DTX), a potent antagonist of Kv1-type potassium channels, to chick brain stem slices in vitro during whole-cell patch clamp recordings. We found a cell-type specific subset of NA neurons were sensitive to DTX: single-spiking NA neurons were most profoundly affected, as well as a subset of tonic firing neurons. Both tonic I (phasic onset bursting) and tonic II (delayed firing) neurons showed DTX sensitivity in their firing rate and phenotypical firing pattern. Tonic III neurons were unaffected. Spike time reliability and fluctuation sensitivity measured in DTX-sensitive NA neurons was also reduced with DTX. Finally, DTX reduced spike threshold adaptation in these neurons, suggesting that GKLT contributes to the temporal properties that allow coding of rapid changes in the inputs to NA neurons. These results suggest that variation in Kv1 channel expression may be a key factor in functional diversity in the avian cochlear nucleus.