TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2.

The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis. The inhibition of IRE1α in the MCL cell line HMC-1.2 has anti-proliferative and pro-apoptotic effects, motivating us to elucidate the IRE1α interactors/regulators in HMC-1.2 cells. Therefore, the TurboID proximity labeling technique combined with MS analysis was applied. Gene Ontology and pathway enrichment analyses revealed that the majority of the enriched proteins are involved in vesicle-mediated transport, protein stabilization, and ubiquitin-dependent ER-associated protein degradation pathways. In particular, the AAA ATPase VCP and the oncoprotein MTDH as IRE1α-interacting proteins caught our interest for further analyses. The pharmacological inhibition of VCP activity resulted in the increased stability of IRE1α and MTDH as well as the activation of IRE1α. The interaction of VCP with both IRE1α and MTDH was dependent on ubiquitination. Moreover, MTDH stability was reduced in IRE1α-knockout cells. Hence, pharmacological manipulation of IRE1α-MTDH-VCP complex(es) might enable the treatment of MCL.

Continuous intraoperative neuromonitoring of the facial nerve predicts postoperative facial palsy in parotid surgery: a prospective study.

PURPOSE: Facial palsy (FP) is the most significant complication of parotidectomy. Currently, the use of intermittent intraoperative neuromonitoring (iIONM) in parotid surgery facilitates nerve detection, which is paramount to nerve protection. Continuous IONM (cIONM), as applied in thyroid surgery, enables real-time information on electrophysiological nerve status through continuous nerve stimulation, thereby allowing consequent amplitude analysis. To date, the application of cIONM in parotid surgery has not been noted in literature. METHODS: We performed parotidectomies with anterograde facial nerve visualization using cIONM in 32 consecutive patients in a prospective study (German Register of clinical studies-DRKS 00011051) during the period October 2016 to January 2020. After the facial trunk had been exposed, an atraumatic stimulation electrode was placed and the nerve was stimulated at 3 Hz, at a low threshold (0.62 ± 0.06 mA), for the entire duration of the preparation. Selected electrophysiological parameters were collected and compared to postoperative facial nerve function, measured by the House-Brackmann grading system. RESULTS: In the post hoc analysis, a significant correlation between a drop in amplitude (< 50% of the "baseline" amplitude) and postoperative FP was recorded (p = 0.001). True positive prediction of FP was noted in 14 out of 16 patients and true negative in 10 out of 16. The sensitivity was 87.5% (AUC 0.75), with a high negative predictive value of 83.3%. CONCLUSION: cIONM has significant value in predicting postoperative FP in parotidectomy. Future development of an acoustic/optic warning system in IONM devices could prevent nerve injury in real time.

Capitalizing on paradoxical activation of the mitogen-activated protein kinase pathway for treatment of Imatinib-resistant mast cell leukemia.

Prevention of fatal side effects during cancer therapy of cancer patients with high-dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug-mediated dimerization of RAF kinases can be the cause of acquired resistance, also called "paradoxical activation." In the present work we re-analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib-resistant, KIT V560G, D816V-expressing human mast cell (MC) leukemia (MCL) cell line HMC-1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF-CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC-1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSAKIT D816V and in KIT D816V hematopoietic progenitors obtained from patient-derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT-driven Imatinib resistance and possible TKI-induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co-treatment, potentially reducing the negative side effects associated with MCL therapy.

Basal Cell Carcinoma of the Head and Neck-A Retrospective Single-Centre Comparison of the Recurrence Rate after R0 or R1 Resection.

The treatment guidelines for basal cell carcinoma (BCC) postulate complete surgical excision using microscopically controlled resection (MOHS) as the gold standard. The need to obtain a small safety margin in the complex anatomical area of the head and neck is very challenging due to the individual characteristics (localization, histology, and size) of tumors and the fact that the postoperative loss of quality of life depends on the surgical defect size. The R1 status is histopathologically defined when the safety margin is less than 1 mm even if there are no tumor cells actually infiltrating the resection margin. Therefore, some studies have already favored a watch-and-wait-strategy in R1 situations. We aimed to evaluate the outcome and recurrence rate of resected BCCs of the head and neck, especially in a histologically proven R1 situation. The outcomes of all resected BCCs observed during a 5-year period (January 2009-December 2013) in a tertiary care center were analyzed. Our standard operating procedure was microscopically controlled surgical excision with reresections until an R0 situation was achieved. In selected patients, an R1 status has been accepted after at least two resections. From the included 191 BCCs, the R1 status was accepted as the final result in 46 (24.1%) cases which had surgically clear margins and were closely followed-up. From 54 patients in the R0 and 40 patients in the R1 group who completed the follow-up (2.4 ± 0.4 years), we observed 0 and 2 local recurrences, respectively (p = 0.19). In cases where frequent follow-up can be secured and the surgical area is delicate, a surgical closure at R1 status can be justified as the recurrence rate is not significantly higher compared with R0.

The pattern of epistaxis recurrence in patients taking prophylactic acetylsalicylic acid (ASA) from a 10 year cohort.

OBJECTIVES: Epistaxis is the most common otolaryngological emergency and one-third of epistaxis patients regularly take low-dose acetylsalicylic acid (ASA) for the prevention of cardiovascular disease (CVD). The shift in contemporary guidelines identifies little benefit of ASA intake in patients who have not previously had an infarction. Existing evidence confirms ASA intake as a factor for severe epistaxis, while the evidence concerning its impact on recurrence is ambiguous. There are no available studies which justify the administration of these drugs nor are there any studies correlating the effects of these drugs to the SCORE2 CVD risk stratifying scale. STUDY DESIGN: A retrospective analysis of all admitted epistaxis patients in a tertiary academic hospital for the 10 year period 2011 to 2021. METHODS: Patient data were analysed using the hospital information software. A recurrence was defined as an epistaxis episode requiring hospital readmittance for at least one night. Patients taking anticoagulants were excluded (N = 421). RESULTS: 444 patients were included: 246 were taking ASA and 198 were not (NoASA). ASA patients had more frequent recurrence in general (p = 0.03), more recurrences per patient (p = 0.002), and more changes in bleeding localisation (p = 0.04). Recurrence in the ASA group was associated with lower haemoglobin values (HR 0.62, p < 0.0001), while surgery (HR 6.83, p < 0.0001) was associated with recurrence in the NoASA group. ASA patients had a statistically significant (r 0.33, p = 0.032) correlation between the total number of epistaxis recurrences and SCORE2. The indication for drug intake was highly questionable in as much as 40% of ASA patients. Follow-up time was 5.27 years. CONCLUSIONS: Epistaxis patients taking prophylactic ASA are significantly more burdened by recurrence, because they have more frequent recurrences, a greater number of recurrences per patient, and more changes in bleeding localisations when compared to control patients. The drug indication is questionable in up to 40% of ASA patients, exposing them unnecessarily to recurrence.

Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells.

The endoplasmic reticulum (ER) is a dynamic organelle that responds to demand in secretory proteins by undergoing expansion. The mechanisms that control the homeostasis of ER size and function involve the activation of the unfolded protein response (UPR). The UPR plays a role in various effector functions of immune cells. Mast cells (MCs) are highly granular tissue-resident cells and key drivers of allergic inflammation. Their diverse secretory functions in response to activation through the high-affinity receptor for IgE (FcεRI) suggest a role for the UPR in their function. Using human cord blood-derived MCs, we found that FcεRI triggering elevated the expression level and induced activation of the UPR transducers IRE1α and PERK, accompanied by expansion of the ER. In mouse bone marrow-derived MCs and peritoneal MCs, the ER underwent a more moderate expansion, and the UPR was not induced following MC activation. The deletion of IRE1α in mouse MCs did not affect proliferation, survival, degranulation, or cytokine stimulation following FcεRI triggering, but it did diminish the surface expression of TLR4 and the consequent response to LPS. A similar phenotype was observed in human MCs using an IRE1α inhibitor. Our data indicate that the ER of MCs, primarily of humans, undergoes a rapid remodeling in response to activation that promotes responses to TLR4. We suggest that IRE1α inhibition can be a strategy for inhibiting the hyperactivation of MCs by LPS over the course of allergic responses.

Influence of Viscose Fibre Geometry on the Structure-Property Relationships of High-Density Polyethylene Composites.

This study investigated the influence of viscose fibre (VF) geometry on the microstructures and resulting properties of high-density polyethylene (HDPE) composites. Seven types of viscose fibres varying in cross-section shape, linear density, and length were pelletised, compounded into HDPE with a twin-screw extruder, and injection moulded. The microstructures of the composites were characterised by investigating their cross-sections and by extracting the fibres and measuring their lengths using optical microscopy (OM). The mechanical and thermal properties of the composites were characterised using differential scanning calorimetry (DSC), tensile tests, Charpy impact tests, and dynamic mechanical analysis (DMA). The composites prepared using cylindrical fibres with a linear density of 1.7 dtex exhibited the best fibre dispersion, highest orientation, and lowest fibre-fibre contact area. The decrease in the linear density of the cylindrical fibres resulted in increasingly worse dispersion and orientation, while composites containing non-cylindrical fibres exhibited a comparably larger fibre-fibre contact area. The initial fibre length of about 3 to 10 mm decreased to the mean values of 0.29 mm to 0.41 mm during processing, depending on the initial geometry. In general, cylindrical fibres exhibited a superior reinforcing effect in comparison to non-cylindrical fibres. The composites containing cylindrical fibres with a linear density of 1.7 dtex and a length of 5 mm exhibited the best reinforcing effect with an increase in tensile modulus and strength of 323% and 141%, respectively.

Erythropoietin Enhances Post-ischemic Migration and Phagocytosis and Alleviates the Activation of Inflammasomes in Human Microglial Cells.

Recombinant human erythropoietin (rhEPO) has been shown to exert anti-apoptotic and anti-inflammatory effects after cerebral ischemia. Inflammatory cytokines interleukin-1ß and -18 (IL-1ß and IL-18) are crucial mediators of apoptosis and are maturated by multiprotein complexes termed inflammasomes. Microglia are the first responders to post-ischemic brain damage and are a main source of inflammasomes. However, the impact of rhEPO on microglial activation and the subsequent induction of inflammasomes after ischemia remains elusive. To address this, we subjected human microglial clone 3 (HMC-3) cells to various durations of oxygen-glucose-deprivation/reperfusion (OGD/R) to assess the impact of rhEPO on cell viability, metabolic activity, oxidative stress, phagocytosis, migration, as well as on the regulation and activation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes. Administration of rhEPO mitigated OGD/R-induced oxidative stress and cell death. Additionally, it enhanced metabolic activity, migration and phagocytosis of HMC-3. Moreover, rhEPO attenuated post-ischemic activation and regulation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes as well as their downstream effectors CASPASE1 and IL-1ß. Pharmacological inhibition of NLRP3 via MCC950 had no effect on the activation of CASPASE1 and maturation of IL-1ß after OGD/R, but increased protein levels of NLRP1, NLRC4, and AIM2, suggesting compensatory activities among inflammasomes. We provide evidence that EPO-conveyed anti-inflammatory actions might be mediated via the regulation of the inflammasomes.

Effects of supervised aerobic exercise on cardiorespiratory fitness and patient-reported health outcomes in colorectal cancer patients undergoing adjuvant chemotherapy-a pilot study.

PURPOSE: Colorectal cancer and its treatment are associated with debilitating side effects. Exercise may improve the physical and psychological wellbeing of cancer patients; however, evidence in colorectal cancer patients undergoing adjuvant chemotherapy is limited. This pilot study aimed to explore the effects of supervised aerobic exercise on cardiorespiratory fitness and patient-reported health outcomes in colorectal cancer patients undergoing adjuvant chemotherapy. METHODS: Patients who had undergone curative resection for colorectal cancer (stages II-III) and were scheduled to receive adjuvant chemotherapy were enrolled into this non-randomized controlled trial. Patients in the intervention group (IG) took part in a 6-month supervised aerobic exercise program, while the control group (CG) received usual care. Cardiorespiratory fitness (measured by peak oxygen consumption) was assessed at baseline and 6 months. Fatigue, quality of life, and physical activity levels were additionally assessed at 3 months. RESULTS: In total, 59 patients (33 in IG vs. 26 in CG) were enrolled into this study. Eighteen patients (9 in IG vs. 9 in CG) dropped out of the study prior to the 6-month follow-up. Significant improvements in cardiorespiratory fitness (p = .002) and selected patient-reported health outcomes, such as reduced motivation (p = .015) and mental fatigue (p = .018), were observed in the IG when compared to the CG. CONCLUSION: To our knowledge, this is the first study to investigate the effects of a supervised aerobic exercise program in colorectal cancer patients undergoing adjuvant chemotherapy. The significant and clinically meaningful improvements in CRF warrant further randomized controlled trials to confirm these findings. TRIALS REGISTRATION: German Clinical Trials Register Identifier: DRKS00005793, 11/03/2014, retrospectively registered.

[Bilateral pedicled gracilis muscle flap and bilateral gluteus muscle flap for multiple-stage reconstruction of vagina, pelvis and perineal region]. / Bilaterale gestielte M. gracilis-Lappenplastik und bilaterale M. gluteus-Rotationslappenplastik zur mehrzeitigen Rekonstruktion der Vagina, des kleinen Beckens sowie der Perinealregion.

Plastic reconstructions of oncological anorectal defects often prove to be very difficult and lead to prolonged hospitalisation due to severe bacterial contamination, neoadjuvant radiotherapy and chemotherapy and difficult anatomical conditions. There is no common standard for plastic reconstruction in such cases. We present a patient diagnosed with distal rectal cancer with infiltration of the anus and vagina, who underwent radical tumour resection of the rectum and anus as well as partial resection of the vagina. A severe necrotising infection occurred post-surgery, which resulted in an extensive defect of the pelvis and perineal region. This article provides a retrospective clinical evaluation and photographic documentation of the reconstruction of the vagina, pelvis and perineal region with a bilateral gracilis and gluteus muscle flap.

Direct oral anticoagulants versus vitamin K antagonists in epistaxis patients: A systematic review and meta-analysis.

OBJECTIVE: Epistaxis is the most common otolaryngological emergency and up to one third of patients in treated on an inpatient basis take oral anticoagulants (OAC). Direct oral anticoagulants (DOAC), an OAC subgroup, have been on the market since 2010 and are being increasingly prescribed due to the cardiological and haematological guidelines that favour them over vitamin K antagonists (VKA), the older of the OAC subgroups. The present study aims to investigate which subgroup of epistaxis patients taking OACs has a more favourable outcome. DESIGN/SETTING: A systematic review and meta-analysis were performed according to the PRISMA 2020 statement using the PubMed and Cochrane Library databases. Continuous data were analysed and standardised mean difference (SMD) was calculated according to Hedges' g. Dichotomous data were analysed, and the Mantel-Haenszel method was applied to establish the odds ratio (OR). Heterogeneity was assessed according to the I2  statistics. MAIN OUTCOME/RESULTS: A total of eight reports covering 1390 patients were included in the final synthesis. The pooled analysis demonstrated significantly shorter hospital stays in the DOAC group (SMD = -0.22, 95% CI-0.42 to -0.02, p = .03) and a significantly higher rate of posterior bleeding in the VKA group (OR = .39, 95% CI 0.23 to 0.68, p = .001). No statistically significant differences with regard to recurrence rates, admission rates, the need for transfusion or surgical intervention (p = .57, .12, .57 and .38 respectively) were found. CONCLUSION: According to this meta-analysis, epistaxis patients taking DOACs have a more favourable outcome than patients taking VKAs.

Clinical Impact of CYFRA 21-1 a Marker for Treatment Failure in Patients With Oropharyngeal Cancer Treated by Radio(chemo)therapy.

BACKGROUND: Primary radio(chemo)therapy [R(C)T] is a treatment option for advanced oropharyngeal squamous cell carcinoma (OSCC). Nevertheless, early diagnostics of treatment failure is problematic. Cytokeratin fragment 19 (CYFRA 21-1), an established marker in the management of pulmonary cancer, might be helpful here. Hence, in this study the impact of CYFRA 21-1 as an indicator for treatment failure and tumor recurrence (TR) in OSCC after R(C)T was analyzed. PATIENTS AND METHODS: The data of 77 patients with advanced OSCC and R(C)T were retrospectively examined. For determination of CYFRA 21-1 at the time of diagnosis and after R(C)T, an electrochemiluminescence immunoassay was used. Tumor residuals and tumor recurrence were pathologically verified after detection by radiological imaging and endoscopy. The mean follow-up was 44.4 months. RESULTS: After R(C)T, 48 (62%) patients showed locoregional control and 29 (38%) patients experienced locoregional failure. No statistical difference in the CYFRA 21-1 level between groups both before (p=0.75) and after R(C)T (p=0.85) was found. Nevertheless, in cases of TR in follow-up, the CYFRA 21-1 level was significantly higher (p≤0.01). The occurrence of TR was significantly associated with a CYFRA 21-1 elevation at this time (p≤0.01). However, CYFRA 21-1 failed to show a suitable discriminative ability for TR (area under the curve=0.57). CONCLUSION: In OSCC, CYFRA 21-1 does not seem to be a useful marker for locoregional failure after R(C)T. Nevertheless, a higher level immediately after R(C)T and in the further course of the disease may be associated with TR in individual patients.

UV light-based reprocessing of flexible endoscopes without working channel in Oto-Rhino-Laryngology: an effective method?

BACKGROUND: Reprocessing of flexible endoscopes (FEs) is often expensive, time consuming, and becomes increasingly complex, due to rising demands of hygiene. After beneficial results in reprocessing of rigid endoscopes using Impelux™ UV-C light technology, we tested the same method for reprocessing of FEs without working channel. MATERIALS AND METHODS: Testing was performed on FEs without working channel after routine clinical use (transnasal flexible endoscopy). Disinfection consisted of mechanical precleaning and 60 s exposure to Impelux™ UV-C light technology. Bacterial contamination was tested on 50 FEs before and after disinfection. Further 50 FEs regarding protein residuals. The absolute effectiveness of the D60 was tested on 50 test bodies (RAMS) with a standardized contamination of 107 colony-forming units (CFU) of Enterococcus faecium. RESULTS: The FEs were contaminated with a high average value of 916.7 CFU (± 1057 CFU) after clinical usage. After reprocessing, an average contamination of 2.8 CFU (± 1.6) on 14% (n = 7) of the FEs was detected consisting of non-pathogenic species, the remaining FE were sterile. After reprocessing, all FEs were protein-free (< 1 µg). The artificially contaminated test bodies showed no remaining bacterial contamination after disinfection, resulting in an average absolute germ reduction of about 107 CFU. CONCLUSION: Impelux™ UV-C light technology efficiently reduces bacterial contamination of FEs and might be useful in daily practice.

Mixed-dimensional InAs nanowire on layered molybdenum disulfide heterostructures via selective-area van der Waals epitaxy.

Self-assembly of vertically aligned III-V semiconductor nanowires (NWs) on two-dimensional (2D) van der Waals (vdW) nanomaterials allows for integration of novel mixed-dimensional nanosystems with unique properties for optoelectronic and nanoelectronic device applications. Here, selective-area vdW epitaxy (SA-vdWE) of InAs NWs on isolated 2D molybdenum disulfide (MoS2) domains is reported for the first time. The MOCVD growth parameter space (i.e., V/III ratio, growth temperature, and total molar flow rates of metalorganic and hydride precursors) is explored to achieve pattern-free positioning of single NWs on isolated multi-layer MoS2 micro-plates with one-to-one NW-to-MoS2 domain placement. The introduction of a pre-growth poly-l-lysine surface treatment is highlighted as a necessary step for mitigation of InAs nucleation along the edges of triangular MoS2 domains and for NW growth along the interior region of 2D micro-plates. Analysis of NW crystal structures formed under the optimal SA-vdWE condition revealed a disordered combination of wurtzite and zinc-blend phases. A transformation of the NW sidewall faceting structure is observed, resulting from simultaneous radial overgrowth during axial NW synthesis. A common lattice arrangement between axially-grown InAs NW core segments and MoS2 domains is described as the epitaxial basis for vertical NW growth. A model is proposed for a common InAs/MoS2 sub-lattice structure, consisting of three multiples of the cubic InAs unit cell along the [21̄1̄] direction, commensurately aligned with a 14-fold multiple of the Mo-Mo (or S-S) spacing along the [101̄0] direction of MoS2 hexagonal lattice. The SA-vdWE growth mode described here enables controlled hybrid integration of mixed-dimensional III-V-on-2D heterostructures as novel nanosystems for applications in optoelectronics, nanoelectronics, and quantum enabling technologies.

UV light-based decontamination: an effective and fast way for disinfection of endoscopes in otorhinolaryngology?

BACKGROUND: Reprocessing of endoscopes becomes increasingly complex, due to rising demands of hygiene. Established methods are often expensive/time-consuming. Recent studies suggest beneficial aspects of disinfection by UV light. In this study we analyzed the efficiency of UV light disinfection of rigid otorhinolaryngological endoscopes. MATERIALS AND METHODS: After mechanical pre-cleaning, the endoscopes were decontaminated for 25 s in the D25 using Impelux™ UV C light technology (UV Smart B.V., Delft, The Netherlands). First, the surface contact samples were taken from 50 used endoscopes to evaluate the bacterial load. Additionally, surface contact samples were taken from further 50 used endoscopes after reprocessing with the D25. Another 50 endoscopes were tested on protein residuals. Furthermore, the absolute effectiveness of the D25 was tested on 50 test bodies (RAMS) with a standardized contamination of 107 colony-forming units (CFU) of Enterococcus faecium. RESULTS: The used endoscopes showed a high bacterial contamination with an average value of 66.908 (± 239.215) CFU. After reprocessing, only a minimal contamination on 10% (n = 5) of the endoscopes with a mean value of 0.12 CFU (± 0.39) was found, resulting in a log-5 reduction in a clinical environment. The documented bacteria were components of the normal skin flora. All tested endoscopes were practically protein-free (< 1 µg). Furthermore, the average absolute germ reduction of the D25 was about 106 CFU on the tested RAMS. CONCLUSION: The D25 UV light system seems to be an effective device for the reprocessing of rigid ORL endoscopes, and therefore, might be suitable for the usage in clinical practice on site.

Clinical relevance of CYFRA 21-1 as a tumour marker in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND: The role of Cytokeratin fraction 21-1 (CYFRA 21-1) as a tumour marker for head and neck cancer is still a matter of research. The aim of the present study was to evaluate the clinical impact of CYFRA 21-1 for patients with oropharyngeal squamous cell carcinoma (OSCC). PATIENTS AND METHODS: Data of 180 patients with an initial diagnosis of OSCC of any stage between 2003 and 2017 were retrospectively analysed regarding the association between pretherapeutic CYFRA 21-1 levels, clinical characteristics, overall and disease-free survival. Additionally, the potential of CYFRA 21-1 for the detection of recurrent disease in the follow-up was evaluated. The cut-off value was set at 3.3 ng/ml. The median follow-up time was 2.85 years. RESULTS: A significant correlation of the CYFRA 21-1 concentration at the time of diagnosis and the N-stage was detected (p = 0.01). Patients with CYFRA 21-1 levels > 3.3 ng/ml at first diagnosis showed a significantly shorter overall survival. In the case of disease-progression, a significant increase of CYFRA 21-1 value was found compared to post-therapeutic CYFRA 21-1 levels (9.1 ng/ml versus 5.1 ng/ml; p < 0.01). CYFRA 21-1 level after treatment showed only a low sensitivity of 32% and a specificity of 78% for tumour recurrence. CONCLUSION: CYFRA 21-1 correlates with the tumour stage and, therefore, the survival of OSCC patients. Posttreatment CYFRA21-1 seems not to be a suitable predictor of tumour recurrence in the further course of the disease. However, a sudden increase of CYFRA 21-1 during follow-up may indicate a tumour recurrence in the individual patient.

Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy.

The integrated stress response (ISR) converges on eIF2α phosphorylation to regulate protein synthesis. ISR is activated by several stress conditions, including endoplasmic reticulum (ER) stress, executed by protein kinase R-like endoplasmic reticulum kinase (PERK). We report that ER stress combined with ISR inhibition causes an impaired maturation of several tyrosine kinase receptors (RTKs), consistent with a partial block of their trafficking from the ER to the Golgi. Other proteins mature or are secreted normally, indicating selective retention in the ER (sERr). sERr is relieved upon protein synthesis attenuation and is accompanied by the generation of large mixed disulfide bonded complexes, including ERp44. sERr was pharmacologically recapitulated by combining the HIV-protease inhibitor nelfinavir with ISRIB, an experimental drug that inhibits ISR. Nelfinavir/ISRIB combination is highly effective to inhibit the growth of RTK-addicted cell lines and hepatocellular (HCC) cells in vitro and in vivo. Thus, pharmacological sERr can be utilized as a modality for cancer treatment.

Correction to: Safety of the "Saxophone®" electrode in parotid surgery for continuous intraoperative neuromonitoring of the facial nerve: results of a pro- and retrospective cohort study.

In the original publication of the article, first name and last names of all authors were swapped.