Diagnostic value of the impairment of olfaction in Parkinson's disease

$\it Background$ Olfactory impairment is increasingly recognized as an early symptom in the development of Parkinson's disease. Testing olfactory function is a non-invasive method but can be time-consuming which restricts its application in clinical settings and epidemiological studies. Here, we investigate odor identification as a supportive diagnostic tool for Parkinson's disease and estimate the performance of odor subsets to allow a more rapid testing of olfactory impairment. $\textit {Methodology/Principal Findings}$ Odor identification was assessed with 16 Sniffin' sticks in 148 Parkinson patients and 148 healthy controls. Risks of olfactory impairment were estimated with proportional odds models. Random forests were applied to classify Parkinson and non-Parkinson patients. Parkinson patients were rarely normosmic (identification of more than 12 odors; 16.8%) and identified on average seven odors whereas the reference group identified 12 odors and showed a higher prevalence of normosmy (31.1%). Parkinson patients with rigidity dominance had a twofold greater prevalence of olfactory impairment. Disease severity was associated with impairment of odor identification (per score point of the Hoehn and Yahr rating OR 1.87, 95% CI 1.26–2.77). Age-related impairment of olfaction showed a steeper gradient in Parkinson patients. $\textit {Coffee, peppermint}$, and $\it anise$ showed the largest difference in odor identification between Parkinson patients and controls. Random forests estimated a misclassification rate of 22.4% when comparing Parkinson patients with healthy controls using all 16 odors. A similar rate (23.8%) was observed when only the three aforementioned odors were applied. $\textit {Conclusions/Significance}$ Our findings indicate that testing odor identification can be a supportive diagnostic tool for Parkinson's disease. The application of only three odors performed well in discriminating Parkinson patients from controls, which can facilitate a wider application of this method as a point-of-care test

Highly immunoreactive IgG antibodies directed against a set of twenty human proteins in the sera of patients with amyotrophic lateral sclerosis identified by protein array

Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, is characterized by the progressive and selective loss of upper and lower motor neurons. Diagnosis of this disorder is based on clinical assessment, and the average survival time is less than 3 years. Injections of IgG from ALS patients into mice are known to specifically mark motor neurons. Moreover, IgG has been found in upper and lower motor neurons in ALS patients. These results led us to perform a case-control study using human protein microarrays to identify the antibody profiles of serum samples from 20 ALS patients and 20 healthy controls. We demonstrated high levels of 20 IgG antibodies that distinguished the patients from the controls. These findings suggest that a panel of antibodies may serve as a potential diagnostic biomarker for ALS

Short-term audiovisual spatial training enhances electrophysiological correlates of auditory selective spatial attention

Audiovisual cross-modal training has been proposed as a tool to improve human spatial hearing. Here, we investigated training-induced modulations of event-related potential (ERP) components that have been associated with processes of auditory selective spatial attention when a speaker of interest has to be localized in a multiple speaker ("cocktail-party") scenario. Forty-five healthy participants were tested, including younger (19–29 years; $\it {n}$ = 21) and older (66–76 years; $\it {n}$ = 24) age groups. Three conditions of short-term training (duration 15 min) were compared, requiring localization of non-speech targets under "cocktail-party" conditions with either (1) synchronous presentation of co-localized auditory-target and visual stimuli (audiovisual-congruency training) or (2) immediate visual feedback on correct or incorrect localization responses (visual-feedback training), or (3) presentation of spatially incongruent auditory-target and visual stimuli presented at random positions with synchronous onset (control condition). Prior to and after training, participants were tested in an auditory spatial attention task (15 min), requiring localization of a predefined spoken word out of three distractor words, which were presented with synchronous stimulus onset from different positions. Peaks of ERP components were analyzed with a specific focus on the N2, which is known to be a correlate of auditory selective spatial attention. N2 amplitudes were significantly larger after audiovisual-congruency training compared with the remaining training conditions for younger, but not older, participants. Also, at the time of the N2, distributed source analysis revealed an enhancement of neural activity induced by audiovisual-congruency training in dorsolateral prefrontal cortex (Brodmann area 9) for the younger group. These findings suggest that cross-modal processes induced by audiovisual-congruency training under "cocktail-party" conditions at a short time scale resulted in an enhancement of correlates of auditory selective spatial attention

Differential interferon-α\alpha subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha ($\alpha$) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFN$\alpha$ subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFN$\alpha$ subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFN$\alpha$5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2–infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFN$\alpha$ subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFN$\alpha$5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2

Immunogenic salivary proteins of Triatoma infestans\textit {Triatoma infestans}

$\textit {Background:}$ Triatomines are vectors of $\textit {Trypanosoma cruzi}$, the etiological agent of Chagas disease in Latin America. The most effective vector, $\textit {Triatoma infestans}$, has been controlled successfully in much of Latin America using insecticide spraying. Though rarely undertaken, surveillance programs are necessary in order to identify new infestations and estimate the intensity of triatomine bug infestations in domestic and peridomestic habitats. Since hosts exposed to triatomines develop immune responses to salivary antigens, these responses can be evaluated for their usefulness as epidemiological markers to detect infestations of $\textit {T. infestans}$. $\textit {Methodology/Principal Findings:}$ $\textit {T. infestans}$ salivary proteins were separated by 2D-gel electrophoresis and tested for their immunogenicity by Western blotting using sera from chickens and guinea pigs experimentally exposed to $\textit {T. infestans}$. From five highly immunogenic protein spots, eight salivary proteins were identified by nano liquid chromatography-electrospray ionization-tandem mass spectrometry (nanoLC-ESI-MS/MS) and comparison to the protein sequences of the National Center for Biotechnology Information (NCBI) database and expressed sequence tags of a unidirectionally cloned salivary gland cDNA library from $\textit {T. infestans}$ combined with the NCBI yeast protein sub-database. The 14.6 kDa salivary protein [gi|149689094] was produced as recombinant protein (r$\it Ti$SP14.6) in a mammalian cell expression system and recognized by all animal sera. The specificity of rTiSP14.6 was confirmed by the lack of reactivity to anti-mosquito and anti-sand fly saliva antibodies. However, r$\it Ti$SP14.6 was recognized by sera from chickens exposed to four other triatomine species, $\textit {Triatoma brasiliensis, T. sordida, Rhodnius prolixus}$, and $\textit {Panstrongylus megistus}$ and by sera of chickens from an endemic area of $\textit {T. infestans}$ and Chagas disease in Bolivia. $\textit {Conclusions/Significance:}$ The recombinant r$\it Ti$SP14.6 is a suitable and promising epidemiological marker for detecting the presence of small numbers of different species of triatomines and could be developed for use as a new tool in surveillance programs, especially to corroborate vector elimination in Chagas disease vector control campaigns

Coinhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription

Pancreatic carcinoma lacks effective therapeutic strategies resulting in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC affects initiation, development, and survival of this tumor type. Using patient-derived xenografts of KRAS- and MYC-driven pancreatic carcinoma, we show that coinhibition of topoisomerase 1 (TOP1) and bromodomain-containing protein 4 (BRD4) synergistically induces tumor regression by targeting promoter pause release. Comparing the nascent transcriptome with the recruitment of elongation and termination factors, we found that coinhibition of TOP1 and BRD4 disrupts recruitment of transcription termination factors. Thus, RNA polymerases transcribe downstream of genes for hundreds of kilobases leading to readthrough transcription. This occurs during replication, perturbing replisome progression and inducing DNA damage. The synergistic effect of TOP1 + BRD4 inhibition is specific to cancer cells leaving normal cells unaffected, highlighting the tumor’s vulnerability to transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of transcription and replication

Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models

$\bf Background$ The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. $\bf Methods$ We analyzed 21 $\textit {KRAS, NRAS, BRAF,}$ and $\it PI3K$ wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways. $\bf Results$ In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies. $\bf Conclusions$ Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC

Lasting response by vertical inhibition with cetuximab and trametinib in KRAS\it KRAS-mutated colorectal cancer patient-derived xenografts

Although approximately half of all metastatic colorectal cancers (mCRCs) harbour mutations in $\it KRAS$ or $\it NRAS$, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS-pathway by targeting epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) in patient-derived xenograft (PDX) tumours with primary $\it KRAS$ mutation. In total, 19 different PDX models comprising 127 tumours were tested. Responses were evaluated according to baseline tumour volume changes and graded as partial response (PR; ≤ − 30%), stable disease (SD; between −30% and +20%) or progressive disease (PD; ≥ + 20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analysed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance (SR). Molecular analyses revealed that primary and SR was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumours. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients

What kind of patients receive inpatient and day-hospital treatment in departments of psychosomatic medicine and psychotherapy in Germany?

$\bf Introduction:$ Germany is one of the few countries with a medical specialty of psychosomatic medicine and psychotherapy and many treatment resources of this kind. $\bf Objective:$ This observational study describes the psychosomatic treatment programs as well as a large sample of day-hospital and inpatients in great detail using structured diagnostic interviews. $\bf Methods:$ Mental disorders were diagnosed according to ICD-10 and DSM-IV by means of Mini-DIPS and SCID-II. In addition to the case records, a modified version of the CSSRI was employed to collect demographic data and service use. The PHQ-D was used to assess depression, anxiety, and somatization. $\bf Results:$ 2,094 patients from 19 departments participated in the study after giving informed consent. The sample consisted of a high proportion of "complex patients" with high comorbidity of mental and somatic diseases, severe psychopathology, and considerable social and occupational dysfunction including more than 50 days of sick leave per year in half of the sample. The most frequent diagnoses were depression, somatoform and anxiety disorders, eating disorders, personality disorders, and somato-psychic conditions. $\bf Conclusions:$ Inpatient and day-hospital treatment in German university departments of psychosomatic medicine and psychotherapy is an intensive multimodal treatment for complex patients with high comorbidity and social as well as occupational dysfunction

The multicenter effectiveness study of inpatient and day hospital treatment in departments of psychosomatic medicine and psychotherapy in Germany

$\bf Background:$ Reliable outcome data of psychosomatic inpatient and day hospital treatment with a focus on psychotherapy are important to strengthen ecological validity by assessing the reality of mental health care in the field. This study aims to evaluate the effectiveness of inpatient and day hospital treatment in German university departments of Psychosomatic Medicine and Psychotherapy in a prospective, naturalistic, multicenter design including structured assessments. $\bf Methods:$ Structured interviews were used to diagnose mental disorders according to ICD-10 and DSM-IV at baseline. Depression, anxiety, somatization, eating disorder and posttraumatic stress disorder (PTSD) symptoms, as well as personality functioning were assessed by means of questionnaires on admission and at discharge. $\bf Results:$ 2,094 patients recruited by 19 participating university hospitals consented to participation in the study. Effect sizes for each of the outcome criteria were calculated for 4–5 sub-groups per outcome domain with differing severity at baseline. Pre-post effect sizes for patients with moderate and high symptom severity at baseline ranged from $\it d$ = 0.78 to $\it d$ = 3.61 with symptoms of PTSD, depression, and anxiety showing the largest and somatization as well as personality functioning showing somewhat smaller effects. $\bf Conclusions:$ Inpatient and day hospital treatment in German university departments of Psychosomatic Medicine and Psychotherapy is effective under field conditions. $\bf Clinical trial registration:$ https://drks.de/search/de/trial/DRKS00016412, identifier: DRKS00016412