Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

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Grandparental genotyping enhances exome variant interpretation

Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband‐only sequencing, mainly due to the rapid identification of de novo disease‐causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X‐inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X‐inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.     

Childhood Cancer and the Risk of ESKD

BackgroundIncreasing cancer incidence among children alongside improved treatments has resulted in a growing number of pediatric cancer survivors. Despite childhood cancer survivors’ exposure to various factors that compromise kidney function, few studies have investigated the association between childhood cancer and future kidney disease.MethodsTo assess the risk of ESKD among childhood cancer survivors, we conducted a nationwide, population-based, retrospective cohort study that encompassed all Israeli adolescents evaluated for mandatory military service from 1967 to 1997. After obtaining detailed histories, we divided the cohort into three groups: participants without a history of tumors, those with a history of a benign tumor (nonmalignant tumor with functional impairment), and those with a history of malignancy (excluding kidney cancer). This database was linked to the Israeli ESKD registry to identify incident ESKD cases. We used Cox proportional hazards models to estimate the hazard ratio (HR) of ESKD.ResultsOf the 1,468,600 participants in the cohort, 1,444,345 had no history of tumors, 23,282 had a history of a benign tumor, and 973 had a history of malignancy. During a mean follow-up of 30.3 years, 2416 (0.2%) participants without a history of tumors developed ESKD. Although a history of benign tumors was not associated with an increased ESKD risk, participants with a history of malignancy exhibited a substantially elevated risk for ESKD compared with participants lacking a history of tumors, after controlling for age, sex, enrollment period, and paternal origin (adjusted HR, 3.2; 95% confidence interval, 1.3 to 7.7).ConclusionsChildhood cancer is associated with an increased risk for ESKD, suggesting the need for tighter and longer nephrological follow-up.     

Semantic memory recognition is supported by intrinsic recollection-like processes: “The butcher on the bus” revisited

Dual-process models suggest that recognition memory is independently supported by recollection and familiarity. Current theories attribute recollection solely to hippocampally mediated episodic memory (EM), and familiarity to both episodic and semantic memory (SM) supported by medial temporal lobe cortex (MTLC) and prefrontal cortex. We tested whether, contrary to this view, recollection-like processes also intrinsically support SM recognition and whether MTL structures are involved in their execution. A semantic Process Dissociation Procedure (PDP) with famous and non-famous names was used in three experiments. Experiment 1 revealed that recollection-like processes in semantic memory were not associated with episodic memory for the public events, were predicted by performance on standard SM tasks and were independent of EM tasks, suggesting they are intrinsic to SM. Experiment 2 demonstrated the independence of the two process estimates by showing only familiarity was affected by shifting response criterion while only recollection estimates were significantly altered under divided-attention. Finally experiment 3 tested amnesic patients with varying degrees of hippocampal and MTLC damage. Despite normal overall fame recognition performance, recollection estimates were specifically affected by MTL damage. When damage was primarily hippocampal, only retrograde recollection estimates were reduced, while more extensive MTLC damage led to both retrograde and anterograde recollection deficits. We conclude that recognition of semantic information is supported by at least two independent processes akin to the ones that support EM recognition. Recollection-like processes are intrinsic to SM and likely do not reflect EM contribution to SM performance. Together with previous studies of recollection in remote memory, these data suggest that recollection is not a unitary phenomenon. In EM it involves autonoetic re-experiencing, and is supported by interaction of fronto-temporal networks; in EM and SM it supports retrieval of contextual/associative information regardless of consciousness type, and is dependent on intact MTL function. Familiarity processes and neural substrates may also differ between lifetime familiarity and within-session familiarity.     

Pain After Spinal Cord Injury Is Associated With Abnormal Presynaptic Inhibition in the Posterior Nucleus of the Thalamus

Pain after spinal cord injury (SCI-Pain) is one of the most debilitating sequelae of spinal cord injury, characterized as relentless, excruciating pain that is largely refractory to treatments. Although it is generally agreed that SCI-Pain results from maladaptive plasticity in the pain processing pathway that includes the spinothalamic tract and somatosensory thalamus, the specific mechanisms underlying the development and maintenance of such pain are yet unclear. However, accumulating evidence suggests that SCI-Pain may be causally related to abnormal thalamic disinhibition, leading to hyperactivity in the posterior thalamic nucleus (PO), a higher-order nucleus involved in somatosensory and pain processing. We previously described several presynaptic mechanisms by which activity in PO is regulated, including the regulation of GABAergic as well as glutamatergic release by presynaptic metabotropic gamma-aminobutyric acid (GABA_B) receptors. Using acute slices from a mouse model of SCI-Pain, we tested whether such mechanisms are affected by SCI-Pain. We reveal 2 abnormal changes in presynaptic signaling in the SCI-Pain condition. The substantial tonic activation of presynaptic GABA_B receptors on GABAergic projections to PO—characteristic of normal animals—was absent in mice with SCI-Pain. Also absent in mice with SCI-Pain was the normal presynaptic regulation of glutamatergic projections to the PO by GABA_B receptors. The loss of these regulatory presynaptic mechanisms in SCI-Pain may be an element of maladaptive plasticity leading to PO hyperexcitability and behavioral pain, and may suggest targets for development of novel treatments.

Diffusion-weighted magnetic resonance enterography for prediction of response to tumor necrosis factor inhibitors in stricturing Crohn’s disease

Background and aims

Distinguishing between fibrotic and inflammatory strictures in Crohn’s disease (CD) is still challenging. The capacity of diffusion-weighted (DWI) magnetic resonance (MRE) to identify intestinal fibrosis was recently demonstrated; however, the therapeutic implications of this association have never been evaluated. The aim of the current study was to identify imaging features, including DWI, which can predict response to anti-inflammatory treatment in patients with stricturing CD.

Methods

Consecutive CD patients with intestinal strictures that initiated treatment with anti-tumor necrosis alpha (anti-TNF) between June 2012 and April 2017 with MRE adjacent to treatment onset were retrospectively collected. The primary outcome was treatment failure, defined as drug discontinuation, CD-related surgery, or endoscopic dilatation of the stricture. Clinical, demographic, and imaging data were compared between patients who did and did not develop treatment failure within 12 months of anti-TNF treatment initiation.

Results

A total of 21 patients were included in the study; 9/21 (42.8%) developed treatment failure. None of the clinical/demographic parameters were associated with the risk of treatment failure. Among imaging parameters, only ADC value (< 1 × 10⁻³ mm²/s) was significantly associated with the risk of treatment failure (AUC = 0.81, 66% vs. 0%, p = 0.015).

Conclusions

Our results suggest that ADC value on DWI MRE may predict the risk of treatment failure in stricturing CD. If replicated in larger studies, these results may guide therapeutic decisions and suggest avoiding anti-TNF treatment.

     

LL-37 Opsonizes and Inhibits Biofilm Formation of Aggregatibacter actinomycetemcomitans at Subbactericidal Concentrations

Host defense peptides are immediate responders of the innate immunity that express antimicrobial, immunoregulatory, and wound-healing activities. Neutrophils are a major source for oral host defense peptides, and phagocytosis by neutrophils is a major mechanism for bacterial clearance in the gingival tissue. Dysfunction of or reduction in the numbers of neutrophils or deficiency in the LL-37 host defense peptide was each previously linked with proliferation of oral Aggregatibacter actinomycetemcomitans which resulted in an aggressive periodontal disease. Surprisingly, A. actinomycetemcomitans shows resistance to high concentrations of LL-37. In this study, we demonstrated that submicrocidal concentrations of LL-37 inhibit biofilm formation by A. actinomycetemcomitans and act as opsonins and agglutinins that greatly enhance its clearance by neutrophils and macrophages. Improved uptake of A. actinomycetemcomitans by neutrophils was mediated by their opsonization with LL-37. Enhanced phagocytosis and killing of A. actinomycetemcomitans by murine macrophage-like RAW 264.7 cells were dependent on their preagglutination by LL-37. Although A. actinomycetemcomitans is resistant to the bactericidal effect of LL-37, our results offer a rationale for the epidemiological association between LL-37 deficiency and the expansion of oral A. actinomycetemcomitans and indicate a possible therapeutic use of cationic peptides for host defense.