Transcriptome-based identification of key actin-binding proteins associated with high metastatic potential in breast cancer.

Introduction: Actin-binding proteins (ABPs) are essential for the regulation of morphological plasticity required for tumor cells to metastasize. The aim of this study was to perform an unbiased bioinformatic approach to identify the key ABPs significantly associated with the metastatic potential of breast cancer cells. Methods: Microarray data from 181 primary breast cancer samples from our hospital were used, and all genes belonging to the Gene Ontology term actin cytoskeleton organization were obtained from QuickGO. Association with metastasis-free survival probability was tested using Cox proportional hazards regression, and pairwise co-expression was tested by Pearson correlations. Differential expression between different subgroups was analyzed using Wilcoxon tests for dichotomous traits and Kruskal-Wallis tests for categorical traits. Validation was performed using four publicly available breast cancer datasets. Results: ARHGAP25 was significantly associated with a low metastatic potential, and CFL1, TMSB15A, and ACTL8 were significantly associated with a high metastatic potential. A significantly higher expression of CFL1, TMSB15A, and ACTL8 mRNA was found in the more aggressive Her2-positive and triple-negative subtypes as well as in ER-negative samples. Also, these genes were co-expressed in the same tumors. However, only mRNA levels of CFL1 were increased in pN1 compared to pN0 patients. External validation revealed that CFL1 and TMSB15A had significant associations with consistent hazard ratios in two breast cancer cohorts, and among these, CFL1 exhibited the highest hazard ratios. Conclusion: CFL1 showed the strongest correlation with the metastatic potential of breast tumors. Thus, targeted inhibition of CFL1 might be a promising approach to treat malignant breast cancer cells.

Efficacy, safety and differential outcomes of immune-chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort.

BACKGROUND: Combined Immuno-chemotherapy consisting of gemcitabine, cisplatin and the programmed death-ligand one inhibitor durvalumab (GCD) is the new standard of care for patients with biliary tract cancers (BTC) based on positive results of the TOPAZ-1 study. OBJECTIVE: We here evaluated the efficacy and safety of GCD for BTC in a German multicenter real-world patient cohort. METHODS: Patients with BTC treated with GCD from 9 German centers were included. Clinicopathological baseline parameters, overall survival (OS), response rate and adverse events (AEs) were retrospectively analyzed. The prognostic impact was determined by Kaplan-Meier analyses and Cox regression models. RESULTS: A total of 165 patients treated with GCD between 2021 and 2024 were included in the study. Median OS and median progression-free survival were 14 months (95% CI 10.3-17.7) and 8 months (95% CI 6.8-9.2), respectively. The best overall response rate was 28.5% and disease control rate was 65.5%. While extrahepatic and intrahepatic BTC showed similar outcomes, mOS was significantly shorter in patients with gall bladder cancer (GB-CA) with 9 months (95% CI 5.5-12.4; p = 0.02). In univariate analyses age ≥70 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥1, status post cholecystectomy, GB-CA and high baseline CRP values were significantly associated with OS. ECOG PS ≥ 1 and GB-CA remained independent prognostic factors for OS in multivariable cox regression analysis. AEs have been reported in 130 patients (78.8%), including 149 grade 3-4 AEs (25.5%). One patient died of severe infectious pneumonia. Immune-related (ir)AEs occurred in 17 patients (10.3%), including 9 grade 3-4 irAEs (2.2%), which led to treatment interruption in 4 patients. CONCLUSIONS: Immuno-chemotherapy in patients with BTC was feasible, effective and safe in a real-life scenario. Our results were comparable to the phase 3 clinical trial results (TOPAZ-1). Reduced efficacy was noted in patients with GB-CA and/or a reduced performance status that warrants further investigation.

In-Hospital Graft Occlusion in Post-Coronary Artery Bypass Grafting Patients in the Early Postoperative Period: A Systematic Review and Meta-Analysis.

Objectives: The objectives of this paper are to evaluate the incidence of early graft occlusion during hospital stays following coronary bypass surgery (CABG) and to assess the factors influencing the odds of in-hospital early graft occlusion. Methods: Reports evaluating the early in-hospital occlusion of coronary bypass grafts were identified through PubMed, Embase, and Cochrane databases. The primary endpoint was to determine the incidence of early graft occlusion following CABG before discharge and to identify and quantify the impact of demographic, clinical, and procedural risk factors on the occurrence of early graft occlusion. The meta-analysis was conducted using a random-effects inverse-variance model with the DerSimonian-Laird estimator, assessing incidence rates, risk factors, and study heterogeneity, with statistical analysis performed using Stata. Results: A total of 22 studies with 35,798 patients were included in the analysis. The overall incidence of in-hospital early graft occlusion was 5% (95% CI: 3% to 7%). In studies using symptom-driven patency assessment, the incidence of occlusion was 2%, whereas in those employing systematic graft patency assessment, it was 6%. Only the presence of a vein graft OR 2.13 (95% CI: 1.19-3.82) was significantly associated with in-hospital graft occlusion. Conclusions: The incidence of in-hospital early graft occlusion seems substantially underestimated if imaging is restricted only to symptomatic patients. Moreover, female gender, increased PI, and the presence of a composite graft could also be potential risk factors for this complication.

A DFT Comparison of C-C Reductive Coupling from Terminal Cyanido and Cyaphido Complexes of Nickel.

The density functional theory study of the thermal C-C reductive coupling from terminal cyanido and hypothetical cyaphido complexes of [Ni(dmpe)] (dmpe = 1,2-bis(dimethylphosphino)ethane) revealed the key reaction intermediate in the reductive C-CP coupling being a σ-CC complex unlike an η2-aryl complex in the Ni C-CN system, as already observed in our previous studies. The reaction in THF is endothermic by 4.9 kcal/mol for cyanido with a 32.0 kcal/mol activation barrier and exothermic by 28.5 kcal/mol for cyaphido with an 11.3 kcal/mol activation barrier. To compare our results with the existing experimental data, we chose mesityl as the aryl group and also studied the CP reaction with [Pt(dmpe)] and [Pt(dmpm)] (dmpe = 1,2-bis(dimethylphosphino)methane) fragments. Our findings are consistent with the thermodynamically uphill photolytic C-CP bond activation in phosphaalkynes with Pt and a faster thermal back-reaction with [Pt(dmpe)] compared to that of [Pt(dmpm)]. Based on the natural population analysis, when the polarity of the C-C bond is inverted, the sign of ΔG° is also inverted.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Sustained Clinical Response to Ivosidenib in Previously Treated Patients with Advanced Intrahepatic Cholangiocarcinoma Harboring an IDH1 R132 Mutation: Two Case Reports.

Introduction: Patients with progressing intrahepatic cholangiocarcinoma (iCCA) harboring an isocitrate dehydrogenase 1 (IDH1) mutation who received ivosidenib showed a median progression-free survival (PFS) benefit of 1.3 months compared to placebo in the phase 3 ClarIDHy trial. Case Presentations: We describe 2 consecutive patients with previously treated unresectable and metastatic iCCA harboring an IDH1 R132 mutation who achieved durable clinical responses with ivosidenib 500 mg once daily for >12 months until disease progression. In one case with a mixed response, a single progressive liver metastasis was additionally treated locally with interstitial brachytherapy, while ivosidenib was continued until further progression. Ivosidenib therapy resulted in long-term disease control with PFS of 20 and 13 months and duration of treatment of 26 and 13 months, respectively, with no relevant side effects. Conclusion: Patients with unresectable or metastatic IDH1-mutated iCCA can achieve sustained clinical responses for >12 months with ivosidenib. No new safety signals were observed during long-term treatment with ivosidenib.

Early silent coronary bypass graft occlusion following coronary bypass surgery, implication of routine coronary computed tomography angiography.

Objective: To evaluate incidence and predictors of early silent bypass occlusion following coronary bypass surgery using cardiac computed tomography angiography. Methods: A total of 439 consecutive patients with mean age of 66 ± 10 years comprising 17% (n = 75) females underwent isolated coronary bypass surgery followed by CT scan before discharge. Graft patency was evaluated in 1,319 anastomoses where 44% (n = 580) arterial and 56% (n = 739) vein graft anastomosis were performed. Cardiovascular risk factors, demographics, and intraoperative variables were analyzed. We conducted univariable and multivariable logistic regression analyses to analyze variables potentially associated with graft occlusion following CABG. Variables included gender, surgery duration, graft flow, pulsatility index, vein vs. artery graft, and recent MI. Results: Overall incidence of graft occlusion was 2.4% (31/1,319), and it was diagnosed in 6.6% (29/439) of patients. The difference in occlusion between arterial (2.1%) and vein (2.6%) grafts was not significant, p = 0.68. The duration of intervention p = 0.034, cross clamp time p = 0.024 as well the number of distal anastomosis p = 0.034 were significantly higher in occlusion group. The univariate and multivariate logistic regression indicated duration of surgery being predictive for bypass graft occlusion with OR = 1.18; 95% CI: 1.01-1.38; p = 0.035. Conclusions: Early graft occlusion was associated with surgical factors. The number of distant anastamoses, along duration of surgical intervention were, significantly influenced the risk of EGO. Prolonged procedural time reflecting complex coronary pathology and time-consuming revascularization procedure was as well associated to the elevated risk of occlusion.

Complications following surgical treatment of ankle fractures in the elderly: can they be avoided?

Background Following surgical treatment of ankle fractures, geriatric patients face high complication rates (CR) in literature. Commonly used diagnostic and treatment algorithms fail to consider requirements of ageing patients which increases the risk of postoperative complications. Objective Present study critically evaluated surgical management of ankle fractures in patients over 65 years old, with focus on identifying modifiable risk factors and effective comorbidity management strategies. Methods We conducted a retrospective single-center study on patients who underwent surgical treatment of an ankle fracture. Based on their age, participants were divided into non-geriatric patients (NGP<65y) and geriatric patients (GP≥65y). We analyzed overall CR and number of minor and major complications in relation to timing of surgery, biological sex, injury pattern, osteosynthesis, pre-existing medical conditions, and postoperative care. Results 402 patients were included. GP encountered significantly higher overall (p<0.001), minor (p<0.001) and major (p=0.003) complications. They presented more complex, displaced and open fractures. Predominant factor contributing to higher CR in NGP and markedly in GP was concomitant diseases, presenting a strong OR of 19,290 (p<0.001) and 17,022 (p<0.001). Delaying surgery and managing comorbidities preoperatively had a favorable impact. Conclusion We revealed a high significant correlation between pre-existing medical conditions and postoperative results. To ascertain viability of delayed surgery in facilitating additional diagnostics and treatment of comorbidities, further comparative trials with a larger cohort are imperative.

Toxicological profile using mass spectrometry in sudden cardiac arrest survivors admitted to a tertiary centre.

BACKGROUND: There has been no previous thorough toxicological examination of a cohort of patients with resuscitated sudden cardiac arrest. We aimed to determine the qualitative and quantitative drug composition in a resuscitated sudden cardiac arrest population, using forensic toxicology, with focus on prescribed, non-prescribed, and commonly abused drugs. METHODS: Individuals aged 18-90 years with resuscitated sudden cardiac arrest of presumed cardiac causes were prospectively included from a single tertiary center. Data from the sudden cardiac arrest hospitalization was collected from medical reports. Drugs used during resuscitation or before the blood sampling were identified and excluded in each patient. Mass spectrometry-based toxicology was performed to determine the absence or presence of most drugs and to quantify the findings. RESULTS: Among 186 consecutively enrolled resuscitated sudden cardiac arrest patients (median age 62 years, 83% male), 90% had a shockable rhythm, and were primarily caused by ischemic heart disease (66%). In total, 90 different drugs (excluding metabolites) were identified, and 82% of patients had at least one drug detected (median of 2 detected drugs (IQR:1-4)) (polypharmacy). Commonly abused drugs were present in 16%, and QT-prolonging drugs were present in 12%. Polypharmacy (≥5drugs) were found in 19% of patients. Importantly, none had potentially lethal concentrations of any drugs. CONCLUSION: In resuscitated sudden cardiac arrest patients with cardiac arrest of presumed cardiac cause, routine toxicological screening provides limited extra information. However, the role of polypharmacy in sudden cardiac arrest requires further investigation. No occult overdose-related cardiac arrests were identified.

Alternative Concepts for Extruded Power Cable Insulation: from Thermosets to Thermoplastics.

The most common type of insulation of extruded high-voltage power cables is composed of low-density polyethylene (LDPE), which must be crosslinked to adjust its thermomechanical properties. A major drawback is the need for hazardous curing agents and the release of harmful curing byproducts during cable production, while the thermoset nature complicates reprocessing of the insulation material. This perspective explores recent progress in the development of alternative concepts that allow to avoid byproducts through either click chemistry type curing of polyethylene-based copolymers or the use of polyolefin blends or copolymers, which entirely removes the need for crosslinking. Moreover, polypropylene-based thermoplastic formulations enable the design of insulation materials that can withstand higher cable operating temperatures and facilitate reprocessing by remelting once the cable reaches the end of its lifetime. Finally, polyethylene-based covalent and non-covalent adaptable networks are explored, which may allow to combine the advantages of thermoset and thermoplastic insulation materials in terms of thermomechanical properties and reprocessability.

Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study.

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD. METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling. RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively. CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Scaffold Matcher: A CMA-ES based algorithm for identifying hotspot aligned peptidomimetic scaffolds.

The design of protein interaction inhibitors is a promising approach to address aberrant protein interactions that cause disease. One strategy in designing inhibitors is to use peptidomimetic scaffolds that mimic the natural interaction interface. A central challenge in using peptidomimetics as protein interaction inhibitors, however, is determining how best the molecular scaffold aligns to the residues of the interface it is attempting to mimic. Here we present the Scaffold Matcher algorithm that aligns a given molecular scaffold onto hotspot residues from a protein interaction interface. To optimize the degrees of freedom of the molecular scaffold we implement the covariance matrix adaptation evolution strategy (CMA-ES), a state-of-the-art derivative-free optimization algorithm in Rosetta. To evaluate the performance of the CMA-ES, we used 26 peptides from the FlexPepDock Benchmark and compared with three other algorithms in Rosetta, specifically, Rosetta's default minimizer, a Monte Carlo protocol of small backbone perturbations, and a Genetic algorithm. We test the algorithms' performance on their ability to align a molecular scaffold to a series of hotspot residues (i.e., constraints) along native peptides. Of the 4 methods, CMA-ES was able to find the lowest energy conformation for all 26 benchmark peptides. Additionally, as a proof of concept, we apply the Scaffold Match algorithm with CMA-ES to align a peptidomimetic oligooxopiperazine scaffold to the hotspot residues of the substrate of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our implementation of CMA-ES into Rosetta allows for an alternative optimization method to be used on macromolecular modeling problems with rough energy landscapes. Finally, our Scaffold Matcher algorithm allows for the identification of initial conformations of interaction inhibitors that can be further designed and optimized as high-affinity reagents.

Masculine depression and its problem behaviors: use alcohol and drugs, work hard, and avoid psychiatry!

The gender role influences vulnerability to mental illness. Substance use, even critical in scale, is perceived as masculine, just like hard (over-)work, while not seeking help. With the ongoing separation between gender and sex, masculine norms become more relevant also to females' mental health. The male depression concept highlights the role of male symptoms in affective disorders. However, the empirical evidence is still limited. Here, we use the denomination 'masculine depression' to open the category for female patients and tested substance use patterns, health services' utilization, and working hours as predictors in a case-control study of 163 depressed in-patients (44% women; masculine vs. non-masculine depression according to a median split of the Male Depression Rating Scale-22) and 176 controls (51% women). We assessed higher depression severity in patients with masculine (vs. non-masculine) depression. Masculine depression (vs. non-masculine depression and vs. no depression) was predicted by more frequent and critical use of alcohol (including binge drinking), tobacco, and illicit drugs, and by longer working times. Moreover, fewer health services contacts due to mental complaints during the previous year were associated with masculine (vs. non-masculine) depression. Alarmingly, even critical substance misuse was not significantly associated with more frequent health services contacts; however, the higher the depression severity, the more contacts the patients reported. Here, we provide evidence that patients with masculine depression are highly burdened and undertreated, which applies equally to female and male patients. This study identified promising targets to establish specialized care offers.

Endoscopic negative-pressure treatment : From management of complications to pre-emptive active reflux drainage in abdomino-thoracic esophageal resection-A new safety concept for esophageal surgery.

INTRODUCTION: Early postoperative reflux (PR) can compromise anastomotic healing after Ivor Lewis esophagectomy (ILE) and poses a risk for aspiration. Anastomotic insufficiency is the most threatening surgical complication. We present the protective method of pre-emptive active reflux drainage (PARD) with simultaneous enteral feeding. We report our experience with this new safety concept in esophageal surgery in a cohort of 43 patients. MATERIALS AND METHODS: For PARD we use a double lumen open porous film drainage (dOFD). To create the dOFD, the gastric tube of a Trelumina probe (Freka®Trelumina, Fresenius) is coated with a double-layered open-pore drainage film (Suprasorb®CNP drainage film, Lohmann & Rauscher) over a length of 25 cm. The dOFD is endoscopically inserted into the tubular stomach intraoperatively after completion of the anastomosis. Continuous negative pressure is applied with an electronic pump (-125 mm Hg). The PR is continuously aspirated completely and the stomach and anastomotic region are decompressed. At the same time, nutrition is delivered via an integrated intestinal tube. Depending on the results of the endoscopic control after 5 days, PARD is either continued or terminated. RESULTS: During the observation period (2017-2023), PARD was used in all patients (n = 43) with ILE. The healing rate under PARD was 100% and healing was observed in all anastomoses. No additional endoscopic procedures or surgical revisions of the anastomoses were required. The median duration of PARD was 8 days (range 4-21). We observed problems in the healing of the anastomosis in 20 of 43 patients (47%) for whom we defined endoscopic criteria for at-risk anastomosis. CONCLUSIONS: Our results suggest that PARD has a strong protective effect on anastomotic healing and may reduce the risk of anastomotic insufficiency. The integrated feeding tube of the dOFD allows early postoperative enteral feeding while simultaneously applying negative pressure. PARD appears to prevent the negative consequences of impaired anastomotic healing.

Pembrolizumab and trastuzumab in combination with FLOT in the perioperative treatment of HER2-positive, localized esophagogastric adenocarcinoma-a phase II trial of the AIO study group (AIO STO 0321).

Background: Esophagogastric adenocarcinoma (EGA) presents a substantial global health challenge as the number of cases continues to rise. The current standard approach for treating localized EGA involves a combination of triplet chemotherapy, which consists of a platinum compound, a fluoropyrimidine, and a taxane (known as FLOT), followed by surgery. In cases of metastatic EGA with HER2-positive status or in certain studies with localized EGA, the use of HER2-targeted antibodies such as trastuzumab has shown improved responses. Recently, the addition of programmed cell death protein 1 (PD-1) inhibitors, such as pembrolizumab, when combined with 5-FU, platinum-based chemotherapy, and trastuzumab, has demonstrated significant enhancements in response rates for HER2-positive metastatic EGA. However, there is currently insufficient evidence regarding this treatment approach in localized HER2-positive disease. Methods: The PHERFLOT study is an open-label, single-arm, multicenter, exploratory phase II trial designed to assess the efficacy, safety, and tolerability of perioperative pembrolizumab, FLOT, and trastuzumab in patients with previously untreated localized HER2-positive EGA. In total, 30 patients will be recruited. The co-primary end points are pathological complete response rate and disease-free survival rate after 2 years. Secondary objectives include safety and tolerability, efficacy in terms of progression-free survival and objective response rate and translational markers, such as blood-based signatures (e.g., immune repertoire changes or emergence of anti-HER2 resistance variants) or microbiota signatures that may correlate with immune activation and therapy response. Discussion: Recent evidence from phase II clinical trials demonstrated improved efficacy through the addition of trastuzumab to perioperative FLOT. Furthermore, in advanced or metastatic EGA, the combination of trastuzumab, FLOT, and the PD1-inhibitor pembrolizumab significantly improved treatment response. The PHERFLOT study aims to assess the efficacy and safety of this treatment approach in HER2-positive-localized EGA, potentially identifying a promising new perioperative regimen for localized EGA, which then needs to be confirmed within a randomized trial. Furthermore, the accompanying translational program of the study might help to improve the stratification of suitable patients and to identify potential translational targets for future clinical trials. Clinical trial registration: https://clinicaltrials.gov, identifier NCT05504720.

Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems-level property in cancer.

The gene dosage compensation hypothesis presents a mechanism through which the expression of certain genes is modulated to compensate for differences in the dose of genes when additional chromosomes are present. It is one of the means through which cancer cells actively cope with the potential damaging effects of aneuploidy, a hallmark of most cancers. Dosage compensation arises through several processes, including downregulation or overexpression of specific genes and the relocation of dosage-sensitive genes. In cancer, a majority of compensated genes are generally thought to be regulated at the translational or post-translational level, and include the basic components of a compensation loop, including sensors of gene dosage and modulators of gene expression. Post-translational regulation is mostly undertaken by a general degradation or aggregation of remaining protein subunits of macromolecular complexes. An increasingly important role has also been observed for transcriptional level regulation. This article reviews the process of targeted gene dosage compensation in cancer and other biological conditions, along with the mechanisms by which cells regulate specific genes to restore cellular homeostasis. These mechanisms represent potential targets for the inhibition of dosage compensation of specific genes in aneuploid cancers. This article critically examines the process of targeted gene dosage compensation in cancer and other biological contexts, alongside the criteria for identifying genes subject to dosage compensation and the intricate mechanisms by which cells orchestrate the regulation of specific genes to reinstate cellular homeostasis. Ultimately, our aim is to gain a comprehensive understanding of the intricate nature of a systems-level property. This property hinges upon the kinetic parameters of regulatory motifs, which we have termed "gene dosage sensor loops." These loops have the potential to operate at both the transcriptional and translational levels, thus emerging as promising candidates for the inhibition of dosage compensation in specific genes. Additionally, they represent novel and highly specific therapeutic targets in the context of aneuploid cancer.

[Persistent olfactory impairment after COVID-19-recommendations of the Working Group on Olfactology and Gustology of the German Society of Oto-rhino-laryngology, Head and Neck Surgery]. / Persistierende Riechminderung nach COVID-19 ­ Empfehlungen der Arbeitsgemeinschaft Olfaktologie und Gustologie der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie e. V.

This article does not intend to comprehensively review the existing literature on coronavirus disease 2019 (COVID-19)-associated smell disorders, but aims to summarize scientific evidence for otorhinolaryngological practice and provide recommendations for diagnosis and treatment of persistent smell disorders following COVID-19.

[Endoscopic negative pressure treatment : From management of complications to pre-emptive active reflux drainage in abdominothoracic esophageal resection-A new safety concept for esophageal surgery]. / Endoskopische Unterdrucktherapie : Vom Komplikationsmanagement zur präemptiven aktiven Refluxdrainage bei abdomino-thorakaler Ösophagusresektion ­ ein neues Sicherheitskonzept für die Ösophaguschirurgie.

INTRODUCTION: Early postoperative reflux (PR) can compromise anastomotic healing after Ivor Lewis esophagectomy (ILE) and poses a risk for aspiration. Anastomotic insufficiency is the most threatening surgical complication. We present the protective method of pre-emptive active reflux drainage (PARD) with simultaneous enteral feeding. We report our experience with this new safety concept in esophageal surgery in a cohort of 43 patients. MATERIALS AND METHODS: For PARD we use a double lumen open porous film drainage (dOFD). To create the dOFD, the gastric tube of a Trelumina probe (Freka®Trelumina, Fresenius) is coated with a double-layered open-pore drainage film (Suprasorb®CNP drainage film, Lohmann & Rauscher) over a length of 25 cm. The dOFD is endoscopically inserted into the tubular stomach intraoperatively after completion of the anastomosis. Continuous negative pressure is applied with an electronic pump (-125 mm Hg). The PR is continuously aspirated completely and the stomach and anastomotic region are decompressed. At the same time, nutrition is delivered via an integrated intestinal tube. Depending on the results of the endoscopic control after 5 days, PARD is either continued or terminated. RESULTS: During the observation period (2017-2023), PARD was used in all patients (n = 43) with ILE. The healing rate under PARD was 100% and healing was observed in all anastomoses. No additional endoscopic procedures or surgical revisions of the anastomoses were required. The median duration of PARD was 8 days (range 4-21). We observed problems in the healing of the anastomosis in 20 of 43 patients (47%) for whom we defined endoscopic criteria for at-risk anastomosis. CONCLUSIONS: Our results suggest that PARD has a strong protective effect on anastomotic healing and may reduce the risk of anastomotic insufficiency. The integrated feeding tube of the dOFD allows early postoperative enteral feeding while simultaneously applying negative pressure. PARD appears to prevent the negative consequences of impaired anastomotic healing.

Man versus machine: Automatic pedicle screw planning using registration-based techniques compared with manual screw planning for thoracolumbar fusion surgeries.

OBJECTIVE: This study evaluates the precision of a commercially available spine planning software in automatic spine labelling and screw-trajectory proposal. METHODS: The software uses automatic segmentation and registration of the vertebra to generate screw proposals. 877 trajectories were compared. Four neurosurgeons assessed suggested trajectories, performed corrections, and manually planned pedicle screws. Additionally, automatic identification/labelling was evaluated. RESULTS: Automatic labelling was correct in 89% of the cases. 92.9% of automatically planned trajectories were in accordance with G&R grade A + B. Automatic mode reduced the time spent planning screw trajectories by 7 s per screw to 20 s per vertebra. Manual mode yielded differences in screw-length between surgeons (largest distribution peak: 5 mm), automatic in contrast at 0 mm. The size of suggested pedicle screws was significantly smaller (largest peaks in difference between 0.5 and 3 mm) than the surgeon's choice. CONCLUSION: Automatic identification of vertebrae works in most cases and suggested pedicle screw trajectories are acceptable. So far, it does not substitute for an experienced surgeon's assessment.

Nanoparticle-Mediated Therapy with miR-198 Sensitizes Pancreatic Cancer to Gemcitabine Treatment through Downregulation of VCP-Mediated Autophagy.

Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo.