TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies

PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation-in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations

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Exosomes and chronic rhinosinusitis

The objective of this manuscripts to review current knowledge regarding exosomes as they relate to the physiology and pathology of the human nose as well as their role as biomarkers of chronic rhinosinusitis with nasal polyps (CRSwNP).Exosomes are 30–150 nm membrane-bound vesicles secreted by virtually all cell types. Exosomes contribute to the rapid inter-epithelial transfer of proteins and mediate innate immunosurveillance and defense mechanisms in the human nasal cavity. Exosomes also protect their cell specific cargo from degradation by nucleases and proteases and mirrorCRS related tissue protein perturbations more effectively than whole mucus. Thus, exosomal isolation and analysis may be used to non-invasively monitor disease severity, prognosis, and potentially even treatment response.Recent studies of exosomes in CRS suggest they can be used to study the immunopathology of chronic sinonasal inflammation. Furthermore, their relative accessibility suggests that exosomal proteomescan be used as non-invasive, serial, and quantitative biosignatures for rhinosinusitis that can be sampled in clinic in order to predict disease severity, prognosis, and treatment response. Exosomal research has also led to important revelations regarding their physiologic function as they seem to play an important role in innate immunosurveillance and defense. However, exosomal research is still nascent and cost-effectiveness as well as feasibility of implementation in the routine workup for CRS have to be further explored

Evaluation of Respiratory Particle Emission during Otorhinolaryngological Procedures in the Context of the SARS-CoV-2 Pandemic

Understanding the risk of infection by routine medical examination is important for the protection of the medical personnel. In this study we investigated respiratory particles emitted by patients during routine otolaryngologic procedures and assessed the risks for the performing physician. We developed two experimental setups to measure aerosol and droplet emission during rigid/flexible laryngoscopy, rhinoscopy, pharyngoscopy, otoscopy, sonography and patient interview for subjects with and without masks. A high-speed-camera setup was used to detect ballistic droplets (approx. > 100 µm) and an aerosol-particle-sizer was used to detect aerosol particles in the range of 0.3 µm to 10 µm. Aerosol particle counts were highly increased for coughing and slightly increased for heavy breathing in subjects without masks. The highest aerosol particle counts occurred during rigid laryngoscopy. During laryngoscopy and rhinoscopy, the examiner was exposed to increased particle emission due to close proximity to the patient’s face and provoked events such as coughing. However, even during sonography or otoscopy without a mask, aerosol particles were expelled close to the examiner. The physician’s exposure to respiratory particles can be reduced by deliberate choice of examination technique depending on medical indication and the use of appropriate equipment for the examiners and the patients (e.g., FFP2 masks for both)

Primary and Secondary/ Metastatic Salivary Duct Carcinoma Presenting within the Sinonasal Tract

Traditionally, sinonasal adenocarcinomas have been subdivided into intestinal (ITAC) and non-intestinal (non-ITAC) categories. The latter encompasses salivary-type adenocarcinomas originating from the seromucinous glands of the sinonasal mucosa and non-salivary adenocarcinomas. The non-salivary adenocarcinoma category is further subdivided into low-and high-grade variants. Among salivary-type sinonasal adenocarcinomas, tumors recapitulating salivary duct carcinoma (SDC) are exceedingly rare, but some might have been lumped into the high-grade non-ITAC category. To date, only three primary SDCs originating in the sinonasal tract have been reported. We herein describe 7 cases of SDC including one previously reported case (4 primary sinonasal, 3 metastatic/ extension from parotid gland SDC). The primary tumors affected 3 males and one female aged 60 - 75. Different sites were involved by the primary tumors while the secondary tumors affected the sphenoidal (2) and the frontal + maxillary (1) sinuses. Three primary tumors were de novo high-grade SDC and one was confined to contours of a pre-existing pleomorphic adenoma. All 3 secondary tumors were SDC ex pleomorphic adenoma of the parotid with a long history of recurrences, ultimately involving the sinonasal tract. Androgen receptor was positive in 7/7 cases. Four of 6 cases were strongly HER2/neu + (either score 3 + or with verified amplification). This small case series adds to the delineation of primary sinonasal SDC highlighting that almost half of invasive SDC presenting within sinonasal tract indeed represents extension or metastasis from a parotid gland primary. There is a tendency towards overrepresentation of HER2/neu-positive cases in both categories (primary and metastatic), but this needs clarification in larger studies

sj-docx-1-ajr-10.1177_19458924221136651 - Supplemental material for Analysis of CRSsNP Proteome Using a Highly Multiplexed Approach in Nasal Mucus

Supplemental material, sj-docx-1-ajr-10.1177_19458924221136651 for Analysis of CRSsNP Proteome Using a Highly Multiplexed Approach in Nasal Mucus by Vanessa-Vivien Pesold, Olaf Wendler, Lisa Morgenthaler, Franziska Gröhn and Sarina K. Mueller in American Journal of Rhinology & Allergy</p

ALK Rearrangements Characterize 2 Distinct Types of Salivary Gland Carcinomas

The majority of salivary gland carcinomas are characterized by recurrent gene fusions that proved highly valuable diagnostically, but only rarely of therapeutic impact. Most of these fusion-positive carcinomas belong to the low-grade or intermediate-grade biological category. To date, only 5 cases of salivary gland carcinomas carrying an oncogenic ALK fusion have been reported in 4 recent studies, but their phenotypic spectrum and their nosological classification remain uncharacterized. We herein describe in detail the clinicopathologic and molecular features of 4 ALK-fusion-positive salivary carcinomas and review previously reported cases to assess if they could be classified into a defined World Health Organization (WHO) category. Patients were 3 men and 1 woman aged from 67 to 79 years (median: 70 y). All tumors originated in the parotid gland. Their size ranged from 1.1 to 3 cm (mean, 2 cm). Three tumors were de novo high-grade salivary duct carcinomas (SDCs) and 1 was a low-grade intercalated-type intraductal carcinoma. Histologically, high-grade tumors were predominantly solid, composed of intimately admixed basal (CK5+, androgen-) and luminal (CK5-, androgen+) components. The remarkable basal component showed squamoid basophilic pattern imparting an adenosquamous-like appearance in all cases. Conventional apocrine intraductal high-grade carcinoma was noted in 1 case. Prominent intraductal growth of the solid basal component (highlighted by p63 staining) was seen in all cases. The tumor cells expressed CK7 (3/3), mammaglobin (3/3, 1 focal), GATA3 (3/3, 1 focal), variably CK5 (3/3), and focally the androgen receptor (1/3), but lacked expression of HER2/neu, SOX10, MUC4, TTF1, S100, and Napsin A. The low-grade tumor showed classic histologic and immunophenotypic features of intercalated-type noninvasive intraductal carcinoma. Molecular profiling showed rearrangements involving exon 20 of ALK in all cases, confirmed by ALK immunohistochemistry (IHC and FISH). The fusion partner was EML4 (n=2) and STRN (n=1) in high-grade tumors and EML4 in the intraductal carcinoma. Two patients with high-grade tumors developed progressive disease (1 died at 9 mo; 1 alive under palliative therapy at 5 mo). This series and a review of 5 published cases indicate that ALK rearrangements characterize 2 distinct subsets of salivary gland carcinomas in the spectrum of high-grade androgen-poor, basal-like SDC (total reported: 5 cases) and low-grade intercalated-type intraductal carcinomas (4 cases). Given the therapeutic relevance of ALK fusions, inclusion of ALK IHC in any atypical-looking or androgen-poor SDC and in high-grade adenocarcinoma-not otherwise specified is recommended. Absence of aberrant ALK expression in genetically characterized secretory (n=15) and intraductal (n=9) carcinomas lacking ALK fusions underlines the value of ALK IHC as a diagnostic screening method for identifying potential cases

ALK Rearrangements Characterize 2 Distinct Types of Salivary Gland Carcinomas: Clinicopathologic and Molecular Analysis of 4 Cases and Literature Review

The majority of salivary gland carcinomas are characterized by recurrent gene fusions that proved highly valuable diagnostically, but only rarely of therapeutic impact. Most of these fusion-positive carcinomas belong to the low-grade or intermediate-grade biological category. To date, only 5 cases of salivary gland carcinomas carrying an oncogenic ALK fusion have been reported in 4 recent studies, but their phenotypic spectrum and their nosological classification remain uncharacterized. We herein describe in detail the clinicopathologic and molecular features of 4 ALK-fusion-positive salivary carcinomas and review previously reported cases to assess if they could be classified into a defined World Health Organization (WHO) category. Patients were 3 men and 1 woman aged from 67 to 79 years (median: 70 y). All tumors originated in the parotid gland. Their size ranged from 1.1 to 3 cm (mean, 2 cm). Three tumors were de novo high-grade salivary duct carcinomas (SDCs) and 1 was a low-grade intercalated-type intraductal carcinoma. Histologically, high-grade tumors were predominantly solid, composed of intimately admixed basal (CK5+, androgen-) and luminal (CK5-, androgen+) components. The remarkable basal component showed squamoid basophilic pattern imparting an adenosquamous-like appearance in all cases. Conventional apocrine intraductal high-grade carcinoma was noted in 1 case. Prominent intraductal growth of the solid basal component (highlighted by p63 staining) was seen in all cases. The tumor cells expressed CK7 (3/3), mammaglobin (3/3, 1 focal), GATA3 (3/3, 1 focal), variably CK5 (3/3), and focally the androgen receptor (1/3), but lacked expression of HER2/neu, SOX10, MUC4, TTF1, S100, and Napsin A. The low-grade tumor showed classic histologic and immunophenotypic features of intercalated-type noninvasive intraductal carcinoma. Molecular profiling showed rearrangements involving exon 20 of ALK in all cases, confirmed by ALK immunohistochemistry (IHC and FISH). The fusion partner was EML4 (n=2) and STRN (n=1) in high-grade tumors and EML4 in the intraductal carcinoma. Two patients with high-grade tumors developed progressive disease (1 died at 9 mo; 1 alive under palliative therapy at 5 mo). This series and a review of 5 published cases indicate that ALK rearrangements characterize 2 distinct subsets of salivary gland carcinomas in the spectrum of high-grade androgen-poor, basal-like SDC (total reported: 5 cases) and low-grade intercalated-type intraductal carcinomas (4 cases). Given the therapeutic relevance of ALK fusions, inclusion of ALK IHC in any atypical-looking or androgen-poor SDC and in high-grade adenocarcinoma-not otherwise specified is recommended. Absence of aberrant ALK expression in genetically characterized secretory (n=15) and intraductal (n=9) carcinomas lacking ALK fusions underlines the value of ALK IHC as a diagnostic screening method for identifying potential cases

sj-docx-2-ajr-10.1177_19458924221136651 - Supplemental material for Analysis of CRSsNP Proteome Using a Highly Multiplexed Approach in Nasal Mucus

Supplemental material, sj-docx-2-ajr-10.1177_19458924221136651 for Analysis of CRSsNP Proteome Using a Highly Multiplexed Approach in Nasal Mucus by Vanessa-Vivien Pesold, Olaf Wendler, Lisa Morgenthaler, Franziska Gröhn and Sarina K. Mueller in American Journal of Rhinology & Allergy</p

Escalation in mucus cystatin 2, pappalysin‐A, and periostin levels over time predict need for recurrent surgery in chronic rhinosinusitis with nasal polyps

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is treated using oral/topical steroids and surgery. Despite maximal medical therapy, some patients remain recalcitrant. Mucus cystatin 2, pappalysin‐A, and periostin can predict the presence of CRSwNP and correlate with disease severity. This study was designed to determine whether prospective sampling of these mucus proteins could predict medical failure and the need for revision surgery. Methods This investigation was an institutional review board‒approved, prospective study of 66 patients with CRSwNP. All patients underwent surgery, administration of topical/oral steroids, and outpatient mucus sampling at 10 time‐points over 2 years. Five proteins, including cystatin 2 (CST2), pappalysin‐A (PAPP‐A), and periostin (PST), were analyzed and correlated with subjective parameters (including scores on the 22‐item Sino‐Nasal Outcomes Test [SNOT‐22]). Variables were then analyzed and compared between those requiring revision surgery within 2 years (n = 5) and those with stable disease (n = 61). Results All patients demonstrated a significant decline in CST2, PAPP‐A, and periostin after their initial surgery. The recalcitrant group demonstrated escalations in all proteins despite steroids, with levels higher than those of the stable group at 1 year (CST2: 258.1 ± 205.2 pg/mL vs 235.3 ± 275.7 pg/mL, p = 0.86; PAPP‐A: 170.3 ± 150.4 pg/mL vs 74.6 ± 106.7 pg/mL, p < 0.05; periostin: 188.8 ± 192.4 ng/mL vs 54.5 ± 47.6 ng/mL, p < 0.001). Escalation in all proteins correlated significantly with worsening SNOT‐22 score at each time‐point (domain 1: 8.2 ± 1.3 vs 5.5 ± 1.1; p < 0.05). Conclusion Early recurrences and medical recalcitrance in CRSwNP may be predicted noninvasively through the serial, prospective sampling of mucus CST2, PAPP‐A, and periostin levels. These biosignatures may help to predict disease course and guide individualized therapy