T-cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination with Pembrolizumab in the Phase 1 KEYNOTE-603 Study.

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed.

Statewide surveillance of Ixodes scapularis (Acari: Ixodidae) for the presence of the human pathogen Borrelia miyamotoi (Spirochaetales: Spirochaetaceae), a relapsing fever spirochete in Pennsylvania, USA, 2019-2020.

Borrelia miyamotoi disease is an emerging tick-borne human illness in the United States caused by Borrelia miyamotoi (Spirochaetales: Spirochaetaceae) bacterium. With Pennsylvania reporting thousands of tick-borne disease cases annually, determining the minimum infection rate (MIR) of B. miyamotoi in Ixodes scapularis (Say, Acari: Ixodidae) adults within Pennsylvania is of utmost importance.

EVIDENCE OF PROTOZOAN AND BACTERIAL INFECTION AND CO-INFECTION AND PARTIAL BLOOD FEEDING IN THE INVASIVE TICK HAEMAPHYSALIS LONGICORNIS IN PENNSYLVANIA.

The Asian longhorned tick, Haemaphysalis longicornis, an invasive tick species in the United States, has been found actively host-seeking while infected with several human pathogens. Recent work has recovered large numbers of partially engorged, host-seeking H. longicornis, which together with infection findings raises the question of whether such ticks can reattach to a host and transmit pathogens while taking additional bloodmeals.

Borrelia burgdorferi Sensu Stricto DNA in Field-Collected Haemaphysalis longicornis Ticks, Pennsylvania, United States.

We collected questing Haemaphysalis longicornis ticks from southeastern counties of Pennsylvania, USA. Of 263 ticks tested by PCR for pathogens, 1 adult female was positive for Borrelia burgdorferi sensu stricto, yielding a 0.4% infection rate.

Targeting CCR8 Induces Protective Antitumor Immunity and Enhances Vaccine-Induced Responses in Colon Cancer.

CCR8 is a chemokine receptor expressed principally on regulatory T cells (Treg) and is known to be critical for CCR8 Treg-mediated immunosuppression. Recent studies have demonstrated that CCR8 is uniquely upregulated in human tumor-resident Tregs of patients with breast, colon, and lung cancer when compared with normal tissue-resident Tregs. Therefore, CCR8 tumor-resident Tregs are rational targets for cancer immunotherapy.

Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging.

The interaction between T cells and the central nervous system (CNS) in homeostasis and injury has been recognized being both pathogenic (CD4+ T-helper 1 - Th1, Th17 and γδT) and ameliorative (Th2 and regulatory T cells - Tregs). However, in-depth studies aimed to elucidate the precise in the aged microenvironment and the dichotomous role of Tregs have just begun and many aspects remain unclear. This is due, not only to a mutual dependency and reciprocal causation of alterations and diseases between the nervous and T cell immune systems, but also to an inconsistent aging of the two systems, which dynamically changes with CNS injury/recovery and/or aging process.

Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation.

Thymic involution and the subsequent amplified release of autoreactive T cells increase the susceptibility toward developing autoimmunity, but whether they induce chronic inflammation with advanced age remains unclear. The presence of chronic low-level proinflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality in virtually every chronic age-related disease. To determine how thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging, we used a Foxn1 conditional knockout mouse model that induces accelerated thymic involution while maintaining a young periphery.

Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice.

FoxN1 is cell-autonomously expressed in skin and thymic epithelial cells (TECs), essential for their development. Inborn mutation of FoxN1 results in hair follicle and TEC development failure, whereas insufficient postnatal FoxN1 expression induces thymic atrophy, resulting in declined T lymphopoiesis. Although upregulating FoxN1 expression in the aged FoxN1-declined thymus rejuvenates T lymphopoiesis, whether its over- and ectopic-expression in early life is beneficial for T lymphopoiesis is unknown.

Leidenfrost levitation: beyond droplets.

Friction is a major inhibitor in almost every mechanical system. Enlightened by the Leidenfrost effect - a droplet can be levitated by its own vapor layer on a sufficiently hot surface - we demonstrate for the first time that a small cart can also be levitated by Leidenfrost vapor. The levitated cart can carry certain amount of load and move frictionlessly over the hot surface.

Insights on FoxN1 biological significance and usages of the "nude" mouse in studies of T-lymphopoiesis.

Mutation in the "nude" gene, i.e. the FoxN1 gene, induces a hairless phenotype and a rudimentary thymus gland in mice (nude mouse) and humans (T-cell related primary immunodeficiency).

Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection.

The hymic medulla plays an essential role in the generation of central tolerance by eliminating self-reactive T-cell clones through thymic negative selection and developing natural regulatory T cells. Age-related FoxN1 decline induces disruption of medullary thymic epithelial cells (mTECs). However, it is unknown whether this perturbs central tolerance to increase autoimmune predisposition in the elderly.

Severity of unhealthy alcohol consumption in medical inpatients and the general population: is the general hospital a suitable place for brief interventions?

Objectives: Evidence for brief interventions in general hospital (GH) settings is scarce, probably due to higher rates of dependent drinkers. The present study aims to compare unhealthy drinking patterns in GH patients with the general population (GP).

Methods: Sample 1 consisted of 4,075 individuals randomly drawn from registration office files, representing the non-institutionalised GP of a northern mixed rural-urban German area.

[Assessment of problematic alcohol use].

An overview with respect to the identification of patients with risky drinking, alcohol abuse or alcohol dependence is given. As a first step, a simple screening questionnaire should be used. Self-statements in standardized questionnaires are more valid than standard laboratory markers.

At-risk and heavy episodic drinking, motivation to change, and the development of alcohol dependence among men.

Objective: The purpose of this study was to analyze whether general hospital inpatients with at-risk and heavy episodic drinking (ARHE) have a higher motivation to change drinking habits and a higher risk of developing alcohol dependence than individuals with at-risk drinking only (AR) or heavy episodic drinking only (HE).

Method: A proactively recruited sample of 425 male general hospital inpatients with AR, HE, or ARHE was used. Men with current alcohol dependence or abuse were excluded.

Reported beverage consumed and alcohol-related diseases among male hospital inpatients with problem drinking.

Aims: The aim of this study was to examine if problem drinkers have varying risks of having alcohol-related diseases according to their reported beverage consumed.

Methods: In a cross-sectional study all consecutive inpatients aged 18- 64 years from four general hospitals of one catchment area were systematically screened for alcohol use. A total of 1011 men with problem drinking were used for this study.

The performance of two motivation measures and outcome after alcohol detoxification.

Aims: The aims of this study were to investigate the performance of the treatment version of the Readiness to Change Questionnaire (RCQ[TV]) among individuals currently receiving alcohol detoxification and to develop a treatment version of the Treatment Readiness Tool (TReaT[TV]).

Methods: A total of 549 patients (86% men) recruited from two detoxification units were interviewed close to treatment intake and followed up 12 months later. Confirmatory factor analyses and logistic regression analyses were conducted.

Predicting utilization of formal and informal help among general hospital inpatients with alcohol use disorders.

Aim: The aim of this prospective study was to identify predictors of utilizing formal and informal help among currently non-help-seeking individuals with alcohol use disorders.

Methods: Data was based on 197 general hospital inpatients with alcohol dependence or abuse. Using multivariable logistic regression analyses, intention to utilize formal help was tested in addition to evidence based predictors of utilization of help.

Alcohol problem drinking among general hospital inpatients in northeastern Germany.

Objective: To estimate proportions of alcohol problem drinking: alcohol use disorders (AUDs) and drinking above recommended levels among general hospital inpatients in northeastern Germany.

Method: The sample includes consecutively admitted inpatients (n=14,332) between 18 and 64 years old. This study adopted a two-stage-sampling approach including screening and ascertainment of diagnosis based on DSM-IV criteria and a quantity-frequency index.

[Health behaviour and health-risk behaviour among job-seekers: a screening at an employment agency].

Aim: The purpose of this study was to investigate the distribution of health behaviours and health-risk behaviours among three groups of job-seeking persons at employment agencies: short-term unemployed, long-term unemployed, and non-unemployed (e.g., threatened by job loss) persons.

Male at-risk drinkers with heavy episodic drinking: a subclinical diagnosis?

Objective: The aim of this study was to examine to what extent general hospital inpatients with risky drinking patterns differ regarding alcohol-associated characteristics. In particular, we tested whether persons with at-risk and heavy episodic drinking (ARHE) differ from those persons with at-risk drinking only (AR) and heavy episodic drinking only (HE).

Method: The participants were recruited using a two-stage sampling process: (1) screening and (2) diagnostic.

Brief alcohol intervention for general hospital inpatients: a randomized controlled trial.

Aim: To test the effectiveness of a brief alcohol intervention among non-dependent general hospital inpatients with alcohol problems, delivered by either a specialized liaison service or hospital physicians.

Method: All inpatients of 29 wards from four general hospitals of one region in Germany were screened for alcohol problems (n=14,332). Of those screening positive, 595 patients were included in a randomized controlled group design using a time-frame.

Dose-response relation between volume of drinking and alcohol-related diseases in male general hospital inpatients.

Aims: Previous studies investigating dose-response relations between volume of drinking and diseases have focused on single diseases only. Until now, the relation between the drinking volume and the risk of having any alcohol-attributable disease is largely unknown. The aim of the present study is to investigate to what extent is the risk of diseases with different alcohol-attributable fractions (AAFs) predicted by daily alcohol consumption (> 120 g, 61-120 g vs 31-60 g).

[Cooperation of general practitioners with priority practices for addiction in Mecklenburg-Western Pommerania].

Objective: The nine "priority practices for addiction" in Mecklenburg-Western Pommerania participating in a model project are supposed to take a central and coordinating position within the addiction management. The aims of this study were to investigate a) the extent to which general practitioners are aware of these priority practices, b) the collaboration among general practices and priority practices and c) the predictors which promote cooperation.

Methods: One third of all general practitioners in Mecklenburg-Western Pommerania (n = 330) were randomly sampled.