Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial.

BACKGROUND: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. METHODS: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. INTERPRETATION: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. FUNDING: Takeda Oncology.

Metabolic control of mitophagy.

Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process known as mitophagy, is vital for mitochondrial homeostasis and cell survival. The central role of mitochondria in cellular metabolism places mitochondrial removal at the interface of key metabolic pathways affecting the biosynthesis or catabolism of acetyl-coenzyme A, nicotinamide adenine dinucleotide, polyamines, as well as fatty acids and amino acids. Molecular switches that integrate the metabolic status of the cell, like AMP-dependent protein kinase, protein kinase A, mechanistic target of rapamycin and sirtuins, have also emerged as important regulators of mitophagy. In this review, we discuss how metabolic regulation intersects with mitophagy. We place special emphasis on the metabolic regulatory circuits that may be therapeutically targeted to delay ageing and mitochondria-associated chronic diseases. Moreover, we identify outstanding knowledge gaps, such as the ill-defined distinction between basal and damage-induced mitophagy, which must be resolved to boost progress in this area.

Right Heart Structure and Function after Electrical Cardioversion for Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) adversely impacts right ventricular (RV) and right atrial (RA) structure and function. There are limited data on these changes after electrical cardioversion (ECV) and the relative contribution of heart rate to evaluate the immediate (1-2 h) and short-term (4-6 weeks) changes in right cardiac chamber dimensions and RV function after ECV in patients with persistent AF. METHODS: Right cardiac chamber dimensions and RV function were measured in 64 patients using transthoracic echocardiography 1-2 h before, immediately after, and 4-6 weeks after ECV. Associations between changes in right-heart measures and rhythm status at follow-up were assessed using linear regression models. RESULTS: For patients who remained in sinus rhythm 4-6 weeks after ECV (n = 48), median fractional area change (FAC) at baseline, immediately after ECV, and 4-6 weeks after ECV were 39 (Q1:35, Q3:42) %, 42 (Q1:39, Q3:46) %, 46 (Q1:43, Q3:49) % (p < 0.01); median tricuspid annular plane systolic excursion (TAPSE) values at the same time points were 18 (Q1:17, Q3:20) mm, 20 (Q1:18, Q3:23) mm, and 24 (Q1:22, Q3:26) mm (p < 0.01), respectively. There was no significant difference in RV end systolic area and RA volume index before and after ECV. However, RV end systolic area and RA volume index decreased significantly after 4-6 weeks from a median of 10 (Q1:8, Q3:13) cm2 to 8 (Q1:7, Q3:10) cm2 (p < 0.01), and from a median of 30 (Q1:24, Q3:36) mL/m2 to 24 (Q1:20, Q3:27) mL/m2 (p < 0.01). Changes in TAPSE were significantly associated with sinus rhythm at follow-up (p = 0.027), changes in FAC showed a strong trend to association with sinus rhythm (p = 0.053), and this was not true for RA measures (p = 0.64). CONCLUSIONS: Among AF patients who remained in sinus rhythm after ECV, RV function improved immediately after ECV with further improvement at 4-6 weeks following sinus rhythm restoration.

Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1.

Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to antibodies targeting programmed cell death protein 1 (PD1) and is characterized by scarce Hodgkin and Reed-Sternberg cells (HRSCs), perpetuating a unique tumor microenvironment (TME). Although anti-PD1 effects appear to be largely mediated by cytotoxic CD8+ T cells in solid tumors, HRSCs frequently lack major histocompatibility complex expression, and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical responses and high interim complete response rates to anti-PD1 based first-line treatment were recently reported for patients with early-stage unfavorable cHL treated in the German Hodgkin Study Group phase 2 NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained from NIVAHL patients before and during the first days of nivolumab first-line cHL therapy. Mirroring the rapid clinical response, HRSCs had disappeared from the tissue within days after the first nivolumab application. The TME already shows a reduction in type 1 regulatory T cells and PD-L1+ tumor-associated macrophages at this early time point of treatment. Interestingly, a cytotoxic immune response and a clonal T-cell expansion were not observed in the tumors or peripheral blood. These early changes in the TME were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL that is suggestive of withdrawal of prosurvival factors, rather than induction of an adaptive antitumor immune response, as the main mechanism of action.

Impact of the first COVID-19 lockdown in Germany on the rate of acute infections during intensive chemotherapy for Hodgkin lymphoma.

PURPOSE: Evidence on the effect of self-protection via social distancing and wearing face-masks on infections during chemotherapy is currently not available. We asked if the occurrence of acute infections during chemotherapy for advanced-stage Hodgkin lymphoma (HL) decreased when COVID-19 protection measures were in effect. METHODS: We analyzed the occurrence of infections during all documented eBEACOPP cycles starting between 01 March and 30 June of 2017 to 2020 in patients treated within the GHSG HD21 study in Germany and compared the infection rates and characteristics by logistic regression models and means of descriptive statistics. RESULTS: We analyzed 911 cycles of 313 adult patients treated with 4 to 6 cycles of eBEACOPP. We found a significant decrease in the occurrence of infections during chemotherapy for HL during COVID-19 lockdown from 131 (19.6%) of 670 cycles in 2017-2019 to 30 (12.6%) of 239 cycles during COVID-19 lockdown [OR 0.574 (95% CI 0.354-0.930), P = 0.024]. The strongest effect was evident for unspecified infections with 39 cycles (5.8%) during 2017-2019 in comparison to 5 cycles (2.1%) during COVID-19 lockdown. 20 (24.1%) of 83 patients had an infection during the COVID-19 lockdown versus 99 (43.2%) of 229 patients in the years 2017-2019 (P = 0.0023). CONCLUSION: The significant decrease of infections during chemotherapy for HL during COVID-19 lockdown reveals the protective measures' potential to shield patients from transmissible pathogens. We conclude that these measures could be recommended for HL patients at risk for infections during chemotherapy.

Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK.

Autophagy, a membrane-dependent catabolic process, ensures survival of aging cells and depends on the cellular energetic status. Acetyl-CoA carboxylase 1 (Acc1) connects central energy metabolism to lipid biosynthesis and is rate-limiting for the de novo synthesis of lipids. However, it is unclear how de novo lipogenesis and its metabolic consequences affect autophagic activity. Here, we show that in aging yeast, autophagy levels highly depend on the activity of Acc1. Constitutively active Acc1 (acc1S/A ) or a deletion of the Acc1 negative regulator, Snf1 (yeast AMPK), shows elevated autophagy levels, which can be reversed by the Acc1 inhibitor soraphen A. Vice versa, pharmacological inhibition of Acc1 drastically reduces cell survival and results in the accumulation of Atg8-positive structures at the vacuolar membrane, suggesting late defects in the autophagic cascade. As expected, acc1S/A cells exhibit a reduction in acetate/acetyl-CoA availability along with elevated cellular lipid content. However, concomitant administration of acetate fails to fully revert the increase in autophagy exerted by acc1S/A Instead, administration of oleate, while mimicking constitutively active Acc1 in WT cells, alleviates the vacuolar fusion defects induced by Acc1 inhibition. Our results argue for a largely lipid-dependent process of autophagy regulation downstream of Acc1. We present a versatile genetic model to investigate the complex relationship between acetate metabolism, lipid homeostasis, and autophagy and propose Acc1-dependent lipogenesis as a fundamental metabolic path downstream of Snf1 to maintain autophagy and survival during cellular aging.

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T-cell function.

Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abl-tyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-γ, TNF-α, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb-specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co-cultured with autologous Mtb-specific T-cells (49±15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification in Mtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support.

Yeast as a tool to identify anti-aging compounds.

In the search for interventions against aging and age-related diseases, biological screening platforms are indispensable tools to identify anti-aging compounds among large substance libraries. The budding yeast, Saccharomyces cerevisiae, has emerged as a powerful chemical and genetic screening platform, as it combines a rapid workflow with experimental amenability and the availability of a wide range of genetic mutant libraries. Given the amount of conserved genes and aging mechanisms between yeast and human, testing candidate anti-aging substances in yeast gene-deletion or overexpression collections, or de novo derived mutants, has proven highly successful in finding potential molecular targets. Yeast-based studies, for example, have led to the discovery of the polyphenol resveratrol and the natural polyamine spermidine as potential anti-aging agents. Here, we present strategies for pharmacological anti-aging screens in yeast, discuss common pitfalls and summarize studies that have used yeast for drug discovery and target identification.

Conventional versus 3-D Echocardiography to Predict Arrhythmia Recurrence After Atrial Fibrillation Ablation.

BACKGROUND: Arrhythmia recurrence after atrial fibrillation (AF) ablation remains high and requires repeat interventions in a substantial number of patients. We assessed the value of conventional and 3-D echocardiography to predict AF recurrence. METHODS AND RESULTS: Consecutive patients undergoing AF ablation by means of pulmonary vein isolation were included in a prospective registry. Echocardiograms were obtained prior to the ablation procedure, and analyzed offline in a standardized manner, including 3-D left atrial (LA) volumetry and determination of LA function and sphericity. The primary endpoint, AF recurrence (>30 seconds) between 3 to 12 months after AF ablation, was independently adjudicated. We included 276 patients (73% male, mean age 59.9 ± 9.9 years). Paroxysmal and persistent AF were present in 178 (64%) and 98 (36%) patients, respectively. Mean left ventricular ejection fraction and indexed LA volume in 3-D (LAVI) were 52 ± 12% and 42 ± 13 mL/m2 , respectively. AF recurrence was observed in 110 (40%) patients after a single procedure. Median (interquartile range) time to AF recurrence was 123 (92; 236) days. In multivariable Cox regression models, the only predictors for AF recurrence were the minimal, maximal, and indexed 3-D LA volumes, P = 0.024, P = 0.016, and P = 0.014, respectively. Quartile specific analysis of 3-D LAVI showed an HR of 1.885 (95%CI 1.066-3.334; P for trend = 0.015) for the highest compared to the lowest quartile. CONCLUSION: Our results show the important role of LA volume for the long-term freedom from arrhythmia after AF ablation. These data also highlight the potential of 3-D echocardiography in this context and may facilitate patient selection for AF ablation.

Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis.

RATIONALE: The development of host-targeted, prophylactic, and therapeutic interventions against tuberculosis requires a better understanding of the immune mechanisms that determine the outcome of infection with Mycobacterium tuberculosis. OBJECTIVES: To identify T-cell-dependent mechanisms that are protective in tuberculosis. METHODS: Multicolor flow cytometry, cell sorting and growth inhibition assays were employed to compare the frequency, phenotype and function of T lymphocytes from bronchoalveolar lavage or the peripheral blood. MEASUREMENTS AND MAIN RESULTS: At two independent study sites, bronchoalveolar lavage cells from donors with latent tuberculosis infection limited the growth of virulent Mycobacterium tuberculosis more efficiently than those in patients who developed disease. Unconventional, glycolipid-responsive T cells contributed to reduced mycobacterial growth because antibodies to CD1b inhibited this effect by 55%. Lipoarabinomannan was the most potent mycobacterial lipid antigen (activation of 1.3% T lymphocytes) and activated CD1b-restricted T cells that limited bacterial growth. A subset of IFN-γ-producing lipoarabinomannan-responsive T cells coexpressed the cytotoxic molecules perforin, granulysin, and granzyme B, which we termed polycytotoxic T cells. Taking advantage of two well-defined cohorts of subjects latently infected with Mycobacterium tuberculosis or patients who developed active disease after infection, we found a correlation between the frequency of polycytotoxic T cells and the ability to control infection (latent tuberculosis infection, 62%; posttuberculosis patients, 26%). CONCLUSIONS: Our data define an unconventional CD8(+) T-cell subset (polycytotoxic T cells) that is based on antigen recognition and function. The results link clinical and mechanistic evidence that glycolipid-responsive, polycytotoxic T cells contribute to protection against tuberculosis.

Rye Bran as a Component in the Diets of Lactating Sows-Effects on Sow and Piglet Performance.

From a cost and sustainability perspective, the use of by-products such as rye bran in sow diets is of particular interest. Rye bran has valuable ingredients that have potential benefits for the gut health of sows. The aim of this study was to investigate the effects of including 15% rye bran in the sows' feed on the performance of sows and piglets. The feeding started one week before the farrowing date and ended at weaning. Performance was evaluated by measuring sow (n = 175) and piglet body weight (n = 1372) and sows' backfat thickness (n = 80). These data were additionally used to calculate the colostrum intake of the suckling piglets and the sows' milk production. It was found that there were no differences in the performance parameters between the experimental and control groups. However, this study showed that the piglets with light birth weight (LBW (<1000 g)) and medium birth weight (MBW (1000-1500 g) consumed more colostrum when the sows were fed rye bran (LBW: C/R 203.0 ± 39.2 g/214.3 ± 35.9 g; MBW: 291.3 ± 39.0 g/298.5 ± 36.4 g). It can be concluded that including 15% rye bran in the feed of lactating sows has no obvious negative effects on the performance of sows and piglets. Further studies are needed to evaluate the possible positive effects of rye bran.

Assessing chronological aging in Saccharomyces cerevisiae.

Chronological age represents the time that passes between birth and a given date. To understand the complex network of factors contributing to chronological lifespan, a variety of model organisms have been implemented. One of the best studied organisms is the yeast Saccharomyces cerevisiae, which has greatly contributed toward identifying conserved biological mechanisms that act on longevity. Here, we discuss high- und low-throughput protocols to monitor and characterize chronological lifespan and chronological aging-associated cell death in S. cerevisiae. Included are propidium iodide staining with the possibility to quantitatively assess aging-associated cell death via flow cytometry or qualitative assessments via microscopy, cell viability assessment through plating and cell counting and cell death characterization via propidium iodide/AnnexinV staining and subsequent flow cytometric analysis or microscopy. Importantly, all of these methods combined give a clear picture of the chronological lifespan under different conditions or genetic backgrounds and represent a starting point for pharmacological or genetic interventions.

Accelerating the Development of Thin Film Photovoltaic Technologies: An Artificial Intelligence Assisted Methodology Using Spectroscopic and Optoelectronic Techniques.

Thin film photovoltaic (TFPV) materials and devices present a high complexity with multiscale, multilayer, and multielement structures and with complex fabrication procedures. To deal with this complexity, the evaluation of their physicochemical properties is critical for generating a model that proposes strategies for their development and optimization. However, this process is time-consuming and requires high expertise. In this context, the adoption of combinatorial analysis (CA) and artificial intelligence (AI) strategies represents a powerful asset for accelerating the development of these complex materials and devices. This work introduces a methodology to facilitate the adoption of AI and CA for the development of TFPV technologies. The methodology covers all the necessary steps from the synthesis of samples for CA to data acquisition, AI-assisted data analysis, and the extraction of relevant information for research acceleration. Each step provides details on the necessary concepts, requirements, and procedures and are illustrated with examples from the literature. Then, the application of the methodology to a complex set of samples from a TFPV production line highlights its ability to rapidly glean significant insights even in intricate scenarios. The proposed methodology can be applied to other types of materials and devices beyond PV and using different characterization techniques.

Process options for the recovery of a pentosan-enriched fraction from wheat-based bioethanol thin stillage.

AIM: Stillage, the main residue from cereal-based bioethanol production, offers a great potential for the recovery of pentosan-type carbohydrates. Therefore, potential process options for the recovery of pentosans from bioethanol thin stillage are investigated and their basic feasibility is demonstrated on a laboratory scale. FINDINGS: The main result of this work is the development of a three-stage process for pentosan recovery, including solid-liquid separation, pentosan solubilisation and purification. The pentosan content of the thin stillage used here was determined to be about 14% related to dry matter (DM). By means of solid-liquid separation, these pentosans accumulate in the liquid phase (up to 80%), while the remainder (about 20%) is found in the solid phase. Solubilisation of these insoluble pentosans was achieved by using either a hydrothermal, an alkaline or an enzymatic treatment. Here, the results indicate a maximum solubilisation yield of 90% with a hydrothermal treatment using liquid hot water at 180 °C. Ultrafiltration and precipitation are investigated for purification. The most promising process option in this study is solid-liquid separation followed by ultrafiltration. In this case, the total pentosan yield is assessed to be about 48% (based on thin stillage) with a final pentosan concentration of about 30%DM.

Molecular targets of spermidine: implications for cancer suppression.

Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermidine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated polyamine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine administration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy, enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunctional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid (ß-oxidation. Through this action, spermidine supplementation is able to restore MTP-mediated mitochondrial respiratory capacity in naïve CD8+ T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.

Rye and Rye Bran as Components of Diets in Piglet Production-Effects on Salmonella Prevalence.

The nutritional benefits of rye (and therefore rye bran) are mainly due to its high content of fermentable dietary fiber, the non-starch polysaccharides (NSP). Microorganisms in the large intestine are able to convert these into short-chain fatty acids (SCFA), including butyrate. Butyrate strengthens the epithelial barrier function in the colon by nourishing the enterocytes and inhibiting the spread of Salmonella in the intestinal tract. Therefore, the aim of this study was to test under field conditions whether a diet with rye or rye bran as the main ingredient for gilts, sows, and weaned piglets is associated with a lower Salmonella prevalence. Depending on the age groups, between 20-30% rye or between 15-20% rye bran was used in the experimental group. A total of n = 1983 boot swabs, n = 356 fecal samples, and n = 1909 serum samples were examined. The results of this study show that rye or rye bran at the levels used had no apparent effect on the number of positive Salmonella samples. However, the Salmonella OD values in the experimental groups were significantly lower than in the control group. This suggests that the use of rye leads to a lower incidence of infection, but this effect could not be proven from swabs.

A hundred spotlights on microbiology: how microorganisms shape our lives.

Viral, bacterial, fungal and protozoal biology is of cardinal importance for the evolutionary history of life, ecology, biotechnology and infectious diseases. Various microbiological model systems have fundamentally contributed to the understanding of molecular and cellular processes, including the cell cycle, cell death, mitochondrial biogenesis, vesicular fusion and autophagy, among many others. Microbial interactions within the environment have profound effects on many fields of biology, from ecological diversity to the highly complex and multifaceted impact of the microbiome on human health. Also, biotechnological innovation and corresponding industrial operations strongly depend on microbial engineering. With this wide range of impact in mind, the peer-reviewed and open access journal Microbial Cell was founded in 2014 and celebrates its 100th issue this month. Here, we briefly summarize how the vast diversity of microbiological subjects influences our personal and societal lives and shortly review the milestones achieved by Microbial Cell during the last years.

Short- and Long-Term Effects of High-Intensity Interval Training vs. Moderate-Intensity Continuous Training on Left Ventricular Remodeling in Patients Early After ST-Segment Elevation Myocardial Infarction-The HIIT-EARLY Randomized Controlled Trial.

Aim: Due to insufficient evidence on the safety and effectiveness of high-intensity interval training (HIIT) in patients early after ST-segment elevation myocardial infarction (STEMI), we aimed to compare short- and long-term effects of randomized HIIT or moderate-intensity continuous training (MICT) on markers of left ventricular (LV) remodeling in STEMI patients receiving optimal guideline-directed medical therapy (GDMT). Materials and Methods: Patients after STEMI (<4 weeks) enrolled in a 12-week cardiac rehabilitation (CR) program were recruited for this randomized controlled trial (NCT02627586). During a 3-week run-in period with three weekly MICT sessions, GDMT was up-titrated. Then, the patients were randomized to HIIT or isocaloric MICT for 9 weeks. Echocardiography and cardiopulmonary exercise tests were performed after run-in (3 weeks), end of CR (12 weeks), and at 1-year follow-up. The primary outcome was LV end-diastolic volume index (LVEDVi) at the end of CR. Secondary outcomes were LV global longitudinal strain (GLS) and cardiopulmonary fitness. Results: Seventy-three male patients were included, with the time between STEMI and start of CR and randomization being 12.5 ± 6.3 and 45.8 ± 10.8 days, respectively. Mixed models revealed no significant group × time interaction for LVEDVi at the end of CR (p = 0.557). However, there was a significantly smaller improvement in GLS at 1-year follow-up in the HIIT compared to the MICT group (p = 0.031 for group × time interaction). Cardiorespiratory fitness improved significantly from a median value of 26.5 (1st quartile 24.4; 3rd quartile 1.1) ml/kg/min at randomization in the HIIT and 27.7 (23.9; 31.6) ml/kg/min in the MICT group to 29.6 (25.3; 32.2) and 29.9 (26.1; 34.9) ml/kg/min at the end of CR and to 29.0 (26.6; 33.3) and 30.6 (26.0; 33.8) ml/kg/min at 1 year follow-up in HIIT and MICT patients, respectively, with no significant group × time interactions (p = 0.138 and 0.317). Conclusion: In optimally treated patients early after STEMI, HIIT was not different from isocaloric MICT with regard to short-term effects on LVEDVi and cardiorespiratory fitness. The worsening in GLS at 1 year in the HIIT group deserves further investigation, as early HIIT may offset the beneficial effects of GDMT on LV remodeling in the long term.

The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity.

Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer's disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42-mediated cell death. We demonstrate that Ydj1/DnaJA1 physically interacts with Abeta42 (in yeast and mouse), stabilizes Abeta42 oligomers, and mediates their translocation to mitochondria. Consequently, deletion of YDJ1 strongly reduces co-purification of Abeta42 with mitochondria and prevents Abeta42-induced mitochondria-dependent cell death. Consistently, purified DnaJ chaperone delays Abeta42 fibrillization in vitro, and heterologous expression of human DnaJA1 induces formation of Abeta42 oligomers and their deleterious translocation to mitochondria in vivo. Finally, downregulation of the Ydj1 fly homologue, Droj2, improves stress resistance, mitochondrial morphology, and memory performance in a Drosophila melanogaster AD model. These data reveal an unexpected and detrimental role for specific HSP40s in promoting hallmarks of Abeta42 toxicity.