Computational modeling of heart failure in microgravity transitions.

The space tourism industry is growing due to advances in rocket technology. Privatised space travel exposes non-professional astronauts with health profiles comprising underlying conditions to microgravity. Prior research has typically focused on the effects of microgravity on human physiology in healthy astronauts, and little is known how the effects of microgravity may play out in the pathophysiology of underlying medical conditions, such as heart failure. This study used an established, controlled lumped mathematical model of the cardiopulmonary system to simulate the effects of entry into microgravity in the setting of heart failure with both, reduced and preserved ejection fraction. We find that exposure to microgravity eventuates an increased cardiac output, and in patients with heart failure there is an unwanted increase in left atrial pressure, indicating an elevated risk for development of pulmonary oedema. This model gives insight into the risks of space flight for people with heart failure, and the impact this may have on mission success in space tourism.

No evidence for a reciprocal relationship between daily self-control failures and addictive behavior in a longitudinal study.

Introduction: We all experience occasional self-control failures (SCFs) in our daily lives, where we enact behaviors that stand in conflict with our superordinate or long-term goals. Based on the assumption that SCFs share common underlying mechanisms with addictive disorders, we tested the hypothesis that a generally higher susceptibility to daily SCFs predicts more addictive behavior, or vice versa. Methods: At baseline, 338 individuals (19-27 years, 59% female) from a community sample participated in multi-component assessments. These included among others (1) a clinical interview on addictive behaviors (quantity of use, frequency of use, DSM-5 criteria; n = 338) and (2) ecological momentary assessment of SCFs (n = 329, 97%). At the 3-year and 6 year follow-up, participation rates for both assessment parts were 71% (n = 240) and 50% (n = 170), respectively. Results: Controlling for age, gender, IQ, and baseline addiction level, random-intercept cross-lagged panel models revealed that participants who reported more SCFs also showed pronounced addictive behavior at the between-person level, but we found no evidence of a predictive relationship at the within-person level over time. Discussion: A higher rate of SCFs is associated with more addictive behavior, while there is no evidence of an intraindividual predictive relationship. Novel hypotheses suggested by additional exploratory results are that (1) only addiction-related SCFs in daily life are early markers of an escalation of use and thus for addictive disorders and that (2) an explicit monitoring of SCFs increases self-reflection and thereby promotes the mobilization of cognitive control in response to goal-desire conflicts.

GDF-15 Suppresses Puromycin Aminonucleoside-Induced Podocyte Injury by Reducing Endoplasmic Reticulum Stress and Glomerular Inflammation.

GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15-deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin-creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15-deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.

Acute kidney failure reveals primary renal non-Hodgkin lymphoma.

A male patient in his 60s was admitted to our hospital with symptoms of dyspnoea, asthenia, diaphoresis and acute kidney failure. No tumour or infection was detected in initial screening. However, laboratory examination suggested that the acute kidney failure was due to an intrarenal cause, exhibiting a tubular injury pattern and indications of tumour lysis syndrome. Initial hydration therapy, paired with intravenous rasburicase, rapidly improved the kidney function. Unfortunately, the kidney function deteriorated once again, prompting a kidney biopsy that revealed an aggressive diffuse large B-cell non-Hodgkin lymphoma of the kidney. The chemotherapy, comprised of R-CHOP scheme, led to a full recovery of the kidney function and complete remission of the lymphoma. Primary renal non-Hodgkin lymphoma without nodal manifestation is rare, and its pathophysiology is poorly understood. Therapy schemes can vary significantly between cases, relying primarily on non-renal-specific haemato-oncological guidelines. Therefore, further studies are needed to develop the best therapeutic approaches.

Gasdermin D drives focal Crystalline Thrombotic Microangiopathy by accelerating Immunothrombosis and Necroinflammation.

Thrombotic microangiopathy (TMA) is characterized by immunothrombosis and life-threatening organ failure, but the precise underlying mechanism driving its pathogenesis remains elusive. In this study, we hypothesized that gasdermin D (GSDMD), a pore-forming protein serving as the final downstream effector of pyroptosis/interleukin (IL)-1pathway, contributes to TMA and its consequences by amplifying neutrophil maturation and subsequent necrosis. Using a murine model of focal crystalline TMA, we found that Gsdmd-deficiency ameliorated immunothrombosis, acute tissue injury and failure. Gsdmd-/- mice exhibited a decrease in mature IL-1, as well as in neutrophil maturation, 2 integrin activation, and recruitment to TMA lesions, where they formed reduced neutrophil extracellular traps both in arteries and interstitial tissue. The GSDMD inhibitor disulfiram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD-deficient human induced pluripotent stem cell-derived neutrophils confirmed the involvement of GSDMD in neutrophil 2 integrin activation, maturation as well as pyroptosis. Both prophylactic and therapeutic administration of disulfiram protected mice from focal TMA, acute tissue injury and failure. Our data identify GSDMD as a key mediator of focal crystalline TMA and its consequences: ischemic tissue infarction and organ failure. GSDMD could potentially serve as a therapeutic target for systemic forms of TMA.

Performance evaluation of the new Sysmex XR-Series haematology analyser.

Background: The new XR-Series haematology analyser from Sysmex provides increased throughput and automation, along with a new reagent in WDF channel for optimised WBC differential. Methods: An analytical performance study for the XR analyser was conducted to evaluate the WDF channel parameters in comparison to the instrument specifications. Additionally, 7460 samples were measured on XR and XN analysers to compare selected parameters and flags, and 930 randomly selected samples were further evaluated with microscopy. Results: All investigated aspects of the analytical performance study for the XR fell within the manufacturer specifications. The correlation coefficients between the two systems for the parameters tested were greater than 0.983 for the main CBC and DIFF parameters, greater than 0.909 for the Extended Inflammation Parameters, and greater than 0.932 for the parameters used in the workflow rulesets of the Extended IPU. Similarly high sensitivities for the detection of abnormal cells were observed for the 'Blasts/Abn Lympho?' flag (XN: 100%, XR: 99.0%) and WPC abnormal flags ('Blasts?' or 'Abn Lympho?') (XN: 97.0%, XR: 96.0%). XN with WPC channel had a 26% reduction of false positive smears compared to XR with 22% reduction, a statistically non-significant difference. Conclusion: The XR analyser had very good analytical performance, and highly comparable results to the predecessor XN analyser in all investigated parameters, flags and workflow aspects.

Bispecific Antibodies in the Treatment of Multiple Myeloma.

The treatment of multiple myeloma (MM) is evolving rapidly. In recent years, T-cell-based novel immunotherapies emerged as new treatment strategies for patients with relapsed/refractory MM, including highly effective new options like chimeric antigen receptor (CAR)-modified T cells and bispecific antibodies (bsAbs). Currently, B-cell maturation antigen is the most commonly used target antigen for CAR T-cell and bsAb therapies in MM. Results from different clinical trials have demonstrated promising efficacy and acceptable safety profile of bsAb in RRMM.

Systematic Investigation of Novel, Controlled Low-Temperature Sintering Processes for Inkjet Printed Silver Nanoparticle Ink.

Functional inks enable manufacturing of flexible electronic devices by means of printing technology. Silver nanoparticle (Ag NP) ink is widely used for printing conductive components. A sintering process is required to obtain sufficient conductivity. Thermal sintering is the most commonly used method, but the heat must be carefully applied to avoid damaging low-temperature substrates such as polymer films. In this work, two alternative sintering methods, damp heat sintering and water sintering are systematically investigated for inkjet-printed Ag tracks on polymer substrates. Both methods allow sintering polyvinyl pyrrolidone (PVP) capped Ag NPs at 85°C. In this way, the resistance is significantly reduced to only 1.7 times that of the samples on polyimide sintered in an oven at 250°C. The microstructure of sintered Ag NPs is analyzed. Taking the states of the capping layer under different conditions into account, the explanation of the sintering mechanism of Ag NPs at low temperatures is presented. Overall, both damp heat sintering and water sintering are viable options for achieving high conductivity of printed Ag tracks. They can broaden the range of substrates available for flexible electronic device fabrication while mitigating substrate damage risks. The choice between them depends on the specific application and the substrate used.

[Chromatic Swept-Source Laser Scanning - Concept for a Cell-Resolving Confocal Laser Slit Lamp?] / Chromatic Swept-Source Laser Scanning ­ Konzept für eine zellauflösende konfokale Laserspaltlampe?

BACKGROUND: The in vivo characterisation of corneal epithelial tissue morphology is of considerable importance for diagnosis, disease prognosis, and the development of a treatment strategy for ocular surface diseases. In contrast to many alternative methods, in vivo corneal confocal microscopy (CCM) not only provides a macroscopic description of the corneal tissue but also allows its visualisation with cellular resolution. However, the translation of CCM from research to clinical practice is significantly limited by the complex and still largely manual operation of available CCM systems. In addition, for cross-sectional images, and analogously to conventional slit lamp microscopy, volume data must be acquired in time-consuming depth scans due to the frontal orientation of the image field in CCM, from which depth slices can subsequently be calculated. The pure acquisition time is already in the range of seconds, and additionally, motion artefacts have to be corrected in a sophisticated way. MATERIALS AND METHODS: This paper presents the concept and optics simulation of a new imaging technique based on a swept-source laser in combination with special chromatic optics. Here, the laser periodically changes its wavelength and is focused at different depths due to the wavelength-dependent aberration of the chromatic optics. RESULTS: The optics simulation results promise good optical resolution at a total imaging depth of 145 µm. CONCLUSION: The long-term goal is cell-resolving in vivo corneal confocal microscopy in real time with differently oriented sectioning directions.

Comparing subtotal parathyroidectomy and total parathyroidectomy with autotransplantation in renal transplant recipients.

Background: Both subtotal parathyroidectomy (SPTX) and total parathyroidectomy with autotransplantation (TPTX + AT) are considered acceptable surgical approaches for renal patients. It is common that parathyroid surgery is performed in patients before they undergo kidney transplantation and there is currently no evidence considering the best surgical approach in this subset of patients. Methods: Two cohorts were identified of consecutive patients who underwent parathyroidectomy for renal hyperparathyroidism by two surgeons at a single institution over equivalent time periods (SPTX and TPTX + AT). A retrospective chart review was performed to assess these techniques, including outcomes following kidney transplantation. Results: There were 125 patients analysed, with 56 patients who underwent SPTX and 69 who underwent TPTX + AT. Both cohorts effectively reduced PTH post operatively. There were 22 patients in the SPTX cohort and 26 in the TPTX + AT cohort that subsequently received kidney transplants. There were no cases of recurrent hyperparathyroidism and one of hypoparathyroidism (4.5%) in the SPTX patients post-transplant. There was one case of recurrent hyperparathyroidism (3.8%) and four of persistent hypoparathyroidism (15.4%) in the TPTX + AT patients post-transplant. Conclusions: Surgery for renal hyperparathyroidism requires a careful balance of the extent of parathyroid resection to prevent persistent/recurrent disease and avoid permanent hypoparathyroidism. SPTX may be a more appropriate option in kidney transplant candidates in order to minimise the risk of long-term hypoparathyroidism.

No NLRP3 inflammasome activity in kidney epithelial cells, not even when the NLRP3-A350V Muckle-Wells variant is expressed in podocytes of diabetic mice.

Background: The NLRP3 inflammasome integrates several danger signals into the activation of innate immunity and inflammation by secreting IL-1ß and IL-18. Most published data relate to the NLRP3 inflammasome in immune cells, but some reports claim similar roles in parenchymal, namely epithelial, cells. For example, podocytes, epithelial cells critical for the maintenance of kidney filtration, have been reported to express NLRP3 and to release IL-ß in diabetic kidney disease, contributing to filtration barrier dysfunction and kidney injury. We questioned this and hence performed independent verification experiments. Methods: We studied the expression of inflammasome components in human and mouse kidneys and human podocytes using single-cell transcriptome analysis. Human podocytes were exposed to NLRP3 inflammasome agonists in vitro and we induced diabetes in mice with a podocyte-specific expression of the Muckle-Wells variant of NLRP3, leading to overactivation of the Nlrp3 inflammasome (Nphs2Cre;Nlrp3A350V) versus wildtype controls. Phenotype analysis included deep learning-based glomerular and podocyte morphometry, tissue clearing, and STED microscopy of the glomerular filtration barrier. The Nlrp3 inflammasome was blocked by feeding ß-hydroxy-butyrate. Results: Single-cell transcriptome analysis did not support relevant NLRP3 expression in parenchymal cells of the kidney. The same applied to primary human podocytes in which NLRP3 agonists did not induce IL-1ß or IL-18 secretion. Diabetes induced identical glomerulomegaly in wildtype and Nphs2Cre;Nlrp3A350V mice but hyperfiltration-induced podocyte loss was attenuated and podocytes were larger in Nphs2Cre;Nlrp3A350V mice, an effect reversible with feeding the NLRP3 inflammasome antagonist ß-hydroxy-butyrate. Ultrastructural analysis of the slit diaphragm was genotype-independent hence albuminuria was identical. Conclusion: Podocytes express low amounts of the NLRP3 inflammasome, if at all, and do not produce IL-1ß and IL-18, not even upon introduction of the A350V Muckle-Wells NLRP3 variant and upon induction of podocyte stress. NLRP3-mediated glomerular inflammation is limited to immune cells.

Lesion-based indicators predict long-term outcomes of pheochromocytoma and paraganglioma- SIZEPASS.

Aim: We seek a simple and reliable tool to predict malignant behavior of pheochromocytoma and paraganglioma (PPGL). Methods: This single-center prospective cohort study assessed size of primary PPGLs on preoperative cross-sectional imaging and prospectively scored specimens using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS). Multiplication of PASS points with maximum lesion diameter (in mm) yielded the SIZEPASS criterion. Local recurrence, metastasis or death from disease were surrogates defining malignancy. Results: 76 consecutive PPGL patients, whereof 58 with pheochromocytoma and 51 female, were diagnosed at a mean age of 52.0 ± 15.2 years. 11 lesions (14.5%) exhibited malignant features at a median follow-up (FU) of 49 months (range 4-172 mo). Median FU of the remaining cohort was 139 months (range 120-226 mo). SIZEPASS classified malignancy with an area under the curve (AUC) of 0.97 (95%CI 0.93-1.01; p<0.0001). Across PPGL, SIZEPASS >1000 outperformed all known predictors of malignancy, with sensitivity 91%, specificity 94%, and accuracy 93%, and an odds ratio of 72 fold (95%CI 9-571; P<0.001). It retained an accuracy >90% in cohorts defined by location (adrenal, extra-adrenal) or mutation status. Conclusions: The SIZEPASS>1000 criterion is a lesion-based, clinically available, simple and effective tool to predict malignant behavior of PPGLs independently of age, sex, location or mutation status.

Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice.

SIGNIFICANCE STATEMENT: We hypothesized that triple therapy with inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression in Col4a3 -deficient mice, a model of Alport syndrome. Late-onset ramipril monotherapy or dual ramipril/empagliflozin therapy attenuated CKD and prolonged overall survival by 2 weeks. Adding the nonsteroidal MR antagonist finerenone extended survival by 4 weeks. Pathomics and RNA sequencing revealed significant protective effects on the tubulointerstitium when adding finerenone to RAS/SGLT2 inhibition. Thus, triple RAS/SGLT2/MR blockade has synergistic effects and might attenuate CKD progression in patients with Alport syndrome and possibly other progressive chronic kidney disorders. BACKGROUND: Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. We hypothesized that triple therapy with RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression. METHODS: We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3 -deficient mice with established Alport nephropathy. Treatment was initiated late (age 6 weeks) in mice with elevated serum creatinine and albuminuria and with glomerulosclerosis, interstitial fibrosis, and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late-onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary end point was mean survival. RESULTS: Mean survival was 63.7±10.0 days (vehicle), 77.3±5.3 days (ramipril), 80.3±11.0 days (dual), and 103.1±20.3 days (triple). Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition. CONCLUSION: Experiments in mice suggest that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive CKDs because of synergistic effects on the glomerular and tubulointerstitial compartments.

Defining the feasibility of same day adrenalectomy - A prospective matched cohort study.

Background: Despite technical advances, day surgery still accounts for <1 % of adrenal procedures. We investigated feasibility and safety of same day adrenalectomy (SDA). Methods: Between We recruited 30 patients with primary hyperaldosteronism (PHA) or Cushing's syndrome (CS) into a prospective matched, single centre cohort study to evaluate the impact of exposure to a same day discharge pathway (SDA cohort; n = 10) or inpatient adrenalectomy (PIPA cohort; n = 20). We compared results to a matched cohort (n = 40) from our prospective in-patient adrenalectomy registry (RIPA cohort). Results: Mean age was 51.3 ± 8.5 years, with 43 % female, 3.3 % ASA I and 96.7 % ASA II. Lesion size was 17 ± 9 mm (range 5-40 mm). 80 % of patients presented with PHA. The predefined primary endpoint (discharge on same calendar day without major complications, emergency presentation or readmission) was achieved in 100 % of SDA, but none of the in-patients (χ2 = 57; p < 0.0001). The secondary endpoint (discharge within 23 h of surgery without major complications, emergency presentation or readmission) was achieved in 100 % of SDA, 90 % of PIPA (n.s.), 33 % of RIPA (33 %; χ2 = 14.6 p < 0.001), and 51.5 % of IPA patients (χ2 = 8.5 p < 0.01). Combining SDA and PIPA cohorts, 93.3 % of treatment episodes met widely used (WHO, United States) definitions of day surgery as completion of the hospital care episode within 23 h. Patients admitted for SDA were highly satisfied (100 %). Conclusion: Same day discharge after adrenalectomy is feasible, safe, and well-perceived in appropriately selected patients with PHA and Cushing's syndrome.

Taxane-Induced Neuropathy and Its Ocular Effects-A Longitudinal Follow-up Study in Breast Cancer Patients.

A common severe neurotoxic side effect of breast cancer (BC) therapy is chemotherapy-induced peripheral neuropathy (CIPN) and intervention is highly needed for the detection, prevention, and treatment of CIPN at an early stage. As the eye is susceptible to neurotoxic stimuli, the present study aims to determine whether CIPN signs in paclitaxel-treated BC patients correlate with ocular changes by applying advanced non-invasive biophotonic in vivo imaging. Patients (n = 14, 10 controls) underwent monitoring sessions after diagnosis, during, and after therapy (T0-T3). Monitoring sessions included general anamnesis, assessment of their quality of life, neurological scores, ophthalmological status, macular optical coherence tomography (OCT), and imaging of their subbasal nerve plexus (SNP) by large-area confocal laser-scanning microscopy (CLSM). At T0, no significant differences were detected between patients and controls. During treatment, patients' scores significantly changed while the greatest differences were found between T0 and T3. None of the patients developed severe CIPN but retinal thickenings could be detected. CLSM revealed large SNP mosaics with identical areas while corneal nerves remained stable. The study represents the first longitudinal study combining oncological examinations with advanced biophotonic imaging techniques, demonstrating a powerful tool for the objective assessment of the severity of neurotoxic events with ocular structures acting as potential biomarkers.

Cell death and barrier disruption by clinically used iodine concentrations.

Povidone-iodine (PVP-I) inactivates a broad range of pathogens. Despite its widespread use over decades, the safety of PVP-I remains controversial. Its extended use in the current SARS-CoV-2 virus pandemic urges the need to clarify safety features of PVP-I on a cellular level. Our investigation in epithelial, mesothelial, endothelial, and innate immune cells revealed that the toxicity of PVP-I is caused by diatomic iodine (I2), which is rapidly released from PVP-I to fuel organic halogenation with fast first-order kinetics. Eukaryotic toxicity manifests at below clinically used concentrations with a threshold of 0.1% PVP-I (wt/vol), equalling 1 mM of total available I2 Above this threshold, membrane disruption, loss of mitochondrial membrane potential, and abolition of oxidative phosphorylation induce a rapid form of cell death we propose to term iodoptosis. Furthermore, PVP-I attacks lipid rafts, leading to the failure of tight junctions and thereby compromising the barrier functions of surface-lining cells. Thus, the therapeutic window of PVP-I is considerably narrower than commonly believed. Our findings urge the reappraisal of PVP-I in clinical practice to avert unwarranted toxicity whilst safeguarding its benefits.

Diagnosis and management of parathyroid carcinoma: a state-of-the-art review.

Parathyroid carcinoma is one of the least common endocrine malignancies and accounts for approximately 1% of all patients with primary hyperparathyroidism. A systematic review of peer-reviewed literature published between January 2000 and March 2022 via Medline, Embase, Cochrane Central Register of Controlled Trials, EudraCT, ClinicalTrials.gov, CINAHL and SCOPUS was conducted. Manuscripts were eligible if they included data on adult non-pregnant populations with parathyroid carcinoma. No restrictions regarding interventions, comparators or duration of follow-up were imposed. Single case reports, reviews or meta-analyses were excluded. Outcomes of interest were molecular pathogenesis, clinical presentation, differential diagnosis, treatment, follow-up and overall survival. Study quality was evaluated using the Newcastle-Ottawa Scale for observational studies. This review included 75 studies from 17 countries, reporting on more than 3000 patients with parathyroid carcinoma. CDC73 mutation has been recognised as playing a pivotal role in molecular pathogenesis. Parathyroid carcinoma typically presents with markedly increased calcium and parathyroid hormone levels. The most frequently described symptoms were bone and muscle pain or weakness. En bloc resection remains the gold standard for the surgical approach. The 5-year overall survival ranged from 60 to 93%, with resistant hypercalcaemia a significant cause of mortality. Emerging evidence indicating that targeted therapy, based on molecular biomarkers, presents a novel treatment option. The rarity of PC and need for personalised treatment warrant multidisciplinary management in a 'centre of excellence' with a track record in PC management.

Genetic Alterations in Members of the Proteasome 26S Subunit, AAA-ATPase (PSMC) Gene Family in the Light of Proteasome Inhibitor Resistance in Multiple Myeloma.

For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM.

Mediastinal Parathyroid Cancer.

Parathyroid cancer (PC) is rare, but its pre-operative recognition is important to choose appropriate access strategies and achieve oncological clearance. This study characterizes features of mediastinal parathyroid cancer (MPC) and explores criteria aiding in the pre-operative recognition of malignancy. We assembled data from 502 patients with mediastinal parathyroid neoplasms (MPNs) from a systematic review of the literature 1968−2020 (n = 467) and our own patient cohort (n = 35). Thirty-two of the 502 MPNs (6.4%) exhibited malignancy. Only 23% of MPC patients underwent oncological surgery. Local persistence and early recurrence at a median delay of 24 months were frequent (45.8%), and associated with a 21.7-fold (95%CI 1.3−351.4; p = 0.03) higher risk of death due to disease. MPCs (n = 30) were significantly larger than cervical PC (n = 330), at 54 ± 36 mm vs. 35 ± 18 mm (χ2 = 20; p < 0.0001), and larger than mediastinal parathyroid adenomas (MPA; n = 226) at 22 ± 15 mm (χ2 = 33; p < 0.01). MPC occurred more commonly in males (60%; p < 0.01), with higher calcium (p < 0.01) and parathyroid hormone (PTH) levels (p < 0.01) than MPA. Mediastinal lesions larger than 3.0 cm and associated with a corrected calcium ≥ 3.0 mM are associated with a more than 100-fold higher odds ratio of being malignant (OR 109.2; 95%CI 1.1−346; p < 0.05). The composite 3 + 3 criterion recognized 74% of all MPC with an accuracy of 83%. Inversely, no MPN presenting with a calcium < 3.0 mM and size < 3.0 cm was malignant. When faced with pHPT in mediastinal location, consideration of the 3 + 3 rule may trigger an oncological team approach based on simple, available criteria.