Development of Subcutaneous Panniculitis-Like T-cell Lymphoma After Immune Checkpoint Inhibitor Treatment.

Program death 1 (PD-1) inhibitors such as nivolumab are immune checkpoint inhibitors that have revolutionized the treatment of metastatic melanoma. Despite its success in treating melanoma, immune activation can lead to immune-related adverse effects, which are experienced by half of melanoma patients treated with PD-1 inhibitors. Despite the common frequency of immune-mediated adverse events, the development of a secondary lymphoma is exceedingly rare. We present the case of a 53-year-old woman diagnosed with stage IV metastatic melanoma, treated with nivolumab, who subsequently developed fatal subcutaneous panniculitis-like T-cell lymphoma (SPTCL).

Off-target effects of statins: molecular mechanisms, side effects and the emerging role of kinases.

Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.

Central Nervous System Prophylaxis Utilization in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma Within a Large Community Health System.

Purpose: The impact of central nervous system (CNS) prophylaxis in diffuse large B-cell lymphoma (DLBCL) is contentious. The CNS International Prognostic Index (IPI) calculator offers prognostic guidance in identifying those patients who may be at highest risk of disease progression or relapse to the CNS. However, it is unclear whether this tool has guided clinician decision-making in a real-world setting. Studies have suggested that CNS prophylaxis may not offer clinically significant benefit in terms of preventing CNS disease progression. Given this, we investigated the utilization of CNS prophylaxis within our own population and documentation of the CNS-IPI score. Methods: We retrospectively evaluated patients with newly diagnosed DLBCL between January 1, 2014, and December 31, 2017. Patients were assessed for receipt of CNS prophylaxis in the form of intrathecal (IT) chemotherapy and/or high-dose intravenous (IV) methotrexate. CNS-IPI scores were calculated for all patients who received CNS prophylaxis or those who experienced CNS disease. Long-term outcomes at five years from diagnosis included CNS progression/relapse and survival. Results: Of 234 patients who met criteria, 20 (8.6%) received either IV methotrexate or IT chemotherapy; most received IT methotrexate. No patients in the IT prophylaxis group developed CNS disease, while two of eight IV methotrexate patients experienced CNS disease involvement. The incidence of CNS progression was 3.7% in the no prophylaxis group and 10% in those who received prophylaxis. Conclusions: This study revealed low utilization of CNS prophylaxis and CNS-IPI documentation in a community hospital system. Given large differences between groups, claims of CNS prophylaxis efficacy are unable to be made. CNS relapse rates were consistent with existing literature and promote continued evaluation of the utility of current CNS prophylaxis approaches in DLBCL. New unambiguously effective therapeutic approaches are needed and may encourage a higher rate of standardized use.

Association between lipoprotein(a), LPA genetic risk score, aortic valve disease, and subsequent major adverse cardiovascular events.

AIMS: Cohort studies have demonstrated associations between calcific aortic valve disease (CAVD) and Lp(a). As Lp(a) is almost entirely genetically determined, in this study, we aim to determine whether Lp(a), when predicted from genetic data, is associated with CAVD and major adverse cardiovascular events (MACEs). METHODS AND RESULTS: Patients undergoing coronary angiography between January 2012 and May 2013 were invited to participate in the study. Of 752 analysable participants, 446 had their Lp(a) measured and 703 had a calculable LPA genetic risk score (GRS). The primary outcomes were the presence of CAVD at baseline and MACE over a 7-year follow-up. The GRS explained 45% of variation in Lp(a). After adjustment for cardiac risk factors and coronary artery disease (CAD), the odds of CAVD increased with increasing Lp(a) [odds ratio (OR) 1.039 per 10-unit increase, 95% confidence interval (CI) 1.022-1.057, P < 0.001] and GRS (OR 1.054 per 10-unit increase, 95% CI 1.024-1.086; P < 0.001). Lipoprotein(a) and the GRS as continuous variables were not associated with subsequent MACEs. A dichotomized GRS (>54) was associated with MACE, but this relationship became non-significant when CAD classification was added into the model (OR 1.333, 95% CI 0.927-1.912; P = 0.12). CONCLUSION: An LPA GRS can explain 45% of variation in Lp(a) levels, and both Lp(a) and the GRS are associated with CAVD. An elevated GRS is associated with future cardiac events in a secondary risk setting, but, if the CAD status is known, it does not provide additional prognostic information.

Lipoprotein (a) [Lp(a)] is a type of cholesterol that is determined almost entirely by genetics. It is associated with heart disease and also stiffening of the heart valves. Recent advancements have made it possible to predict Lp(a) levels by analysing a person's DNA. This study examines the association between genetically predicted Lp(a) and adverse outcomes.Genetically predicted Lp(a) accounts for 45% of the variability in the actual Lp(a) level.Both actual and genetically predicted Lp(a) are associated with heart valve disease and adverse heart outcomes. If the degree of narrowing of the arteries in the heart is already known, genetically predicted Lp(a) does not help further predict risk.

Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is preceded by mitochondrial morphological changes.

Previously, we showed that fluvastatin treatment induces myofibrillar damage and mitochondrial phenotypes in the skeletal muscles of Drosophila. However, the sequential occurrence of mitochondrial phenotypes and myofibril damage remains elusive. To address this, we treated flies with fluvastatin for two and five days and examined their thorax flight muscles using confocal microscopy. In the two-day fluvastatin group, compared to the control, thorax flight muscles exhibited mitochondrial morphological changes, including fragmentation, rounding up and reduced content, while myofibrils remained organized in parallel. In the five-day fluvastatin treatment, not only did mitochondrial morphological changes become more pronounced, but myofibrils became severely disorganized with significantly increased thickness and spacing, along with myofilament abnormalities, suggesting myofibril damage. These findings suggest that fluvastatin-induced mitochondrial changes precede myofibril damage. Moreover, in the five-day fluvastatin group, the mitochondria demonstrated elevated H2O2 and impaired fatty acid oxidation compared to the control group, indicating potential mitochondrial dysfunction. Surprisingly, knocking down Hmgcr (Drosophila homolog of HMGCR) showed normal mitochondrial respiration in all parameters compared to controls or five-day fluvastatin treatment, which suggests that fluvastatin-induced mitochondrial dysfunction might be independent of Hmgcr inhibition. These results provide insights into the sequential occurrence of mitochondria and myofibril damage in statin-induced myopathy for future studies.

Upper-Limb High-Intensity Interval Training or Passive Heat Therapy to Optimize Cardiorespiratory Fitness Prior to Total Hip or Knee Arthroplasty: A Randomized Controlled Trial.

OBJECTIVE: Preoperative exercise training, or prehabilitation, aims to optimize cardiorespiratory fitness before surgery to reduce the risk of adverse perioperative events and delayed recovery. However, traditional exercise such as walking and cycling can be difficult for people with degenerative joint diseases of the lower limbs, such as osteoarthritis. The purpose of this study was to compare the effect of three low-impact interventions on cardiorespiratory fitness, physical function, and subjective health before total hip or knee arthroplasty. METHODS: This was a randomized controlled trial involving 93 participants with severe knee or hip osteoarthritis awaiting joint replacement surgery. Participants underwent cardiopulmonary exercise testing (to measure peak oxygen consumption [ V ̇ $$ \dot{V} $$ O2 ]), then were randomized to heat therapy (Heat; 20-30 min immersed in 40°C water followed by ~15 min light-resistance exercise), high-intensity interval training (HIIT; 6-8 × 60 s intervals on a cross-trainer or arm ergometer at ~90%-100% peak V ̇ $$ \dot{V} $$ O2 ), or home-based exercise (Home; ~15 min light-resistance exercise); for up to 36 sessions (3 sessions per week for 12 weeks). RESULTS: Peak V ̇ $$ \dot{V} $$ O2 increased by 16% across HIIT and to a greater extent than Heat (+2.5 mL × min-1 × kg-1 [95% CI: 0.5-4.4], P = 0.009) and Home (+3.2 mL × min-1 × kg-1 [1.2-5.2], P = 0.001). The anaerobic threshold increased across HIIT (+1.5 mL × min-1 × kg-1 [0.7-2.3], P < 0.001) and Heat (+1.2 mL × min-1 × kg-1 [0.4-1.9], P = 0.004), but not Home (-0.5 mL × min-1 × kg-1 [-1.3 to 0.3], P = 0.248). Subjective severity of osteoarthritis was unchanged with any intervention (P ≥ 0.250). CONCLUSION: Heat therapy and HIIT improved indices of cardiorespiratory fitness preoperatively in patients who have difficulty performing lower-limb exercise.

Outcomes of patients with early calcific aortic valve disease detected by clinically indicated echocardiography.

AIMS: Previous studies have demonstrated relatively slow rates of progression of early calcific aortic valve disease (CAVD), which encompasses aortic sclerosis (ASc) and mild aortic stenosis (AS). The potential evolution to clinically significant AS is unclear, and we therefore examined the long-term outcomes of patients with ASc and mild AS detected at the time of clinically indicated echocardiography. METHODS AND RESULTS: Data from initial clinically indicated echocardiograms performed between 2010 and 2018 in patients aged ≥18 years were extracted and linked to nationally collected outcome data. Those with impaired right or left systolic ventricular function or other significant left-sided valve disease were excluded. A time to first event analysis was performed with a composite primary outcome of cardiovascular death and aortic valve intervention (AVI). Of the 13 313 patients, 8973 had no CAVD, 3436 had ASc, and 455 had mild AS. The remainder had moderate or worse stenosis. Over a median follow-up period of 4.2 (interquartile range 1.8-6.7) years (and after adjustment for age and sex), those with ASc were at greater risk of the primary outcome [hazard ratio (HR) 2.9, 95% confidence interval (CI) 2.1-4.0] and need for AVI (HR 26.8, 95% CI 9.1-79.1) compared with those with no CAVD. Clinical event rates accelerated after ∼5 years in those with mild AS. CONCLUSION: Patients with ASc are >25 times more likely to require AVI than those with no CAVD, and follow-up echocardiography should be considered within 3-4 years in those with mild AS.

Volcaniclastic density currents explain widespread and diverse seafloor impacts of the 2022 Hunga Volcano eruption.

The impacts of large terrestrial volcanic eruptions are apparent from satellite monitoring and direct observations. However, more than three quarters of all volcanic outputs worldwide lie submerged beneath the ocean, and the risks they pose to people, infrastructure, and benthic ecosystems remain poorly understood due to inaccessibility and a lack of detailed observations before and after eruptions. Here, comparing data acquired between 2015 - 2017 and 3 months after the January 2022 eruption of Hunga Volcano, we document the far-reaching and diverse impacts of one of the most explosive volcanic eruptions ever recorded. Almost 10 km3 of seafloor material was removed during the eruption, most of which we conclude was redeposited within 20 km of the caldera by long run-out seafloor density currents. These powerful currents damaged seafloor cables over a length of >100 km, reshaped the seafloor, and caused mass-mortality of seafloor life. Biological (mega-epifaunal invertebrate) seafloor communities only survived the eruption where local topography provided a physical barrier to density currents (e.g., on nearby seamounts). While the longer-term consequences of such a large eruption for human, ecological and climatic systems are emerging, we expect that these previously-undocumented refugia will play a key role in longer-term ecosystem recovery.

Drosophila as a Rapid Screening Model to Evaluate the Hypoglycemic Effects of Dipeptidyl Peptidase 4 (DPP4) Inhibitors: High Evolutionary Conservation of DPP4.

Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, have been an integral part of the treatment of type 2 diabetes mellitus (T2DM) for several years. Despite their remarkable efficacy in lowering glucose levels and their compatibility with other hypoglycemic drugs, recent studies have revealed adverse effects, prompting the search for improved drugs within this category, which has required the use of animal models to verify the hypoglycemic effects of these compounds. Currently, in many countries the use of mammals is being significantly restricted, as well as cost prohibitive, and alternative in vivo approaches have been encouraged. In this sense, Drosophila has emerged as a promising alternative for several compelling reasons: it is cost-effective, offers high experimental throughput, is genetically manipulable, and allows the assessment of multigenerational effects, among other advantages. In this study, we present evidence that diprotin A, a DPP4 inhibitor, effectively reduces glucose levels in Drosophila hemolymph. This discovery underscores the potential of Drosophila as an initial screening tool for novel compounds directed against DPP4 enzymatic activity.

Plasminogen Receptors Promote Lipoprotein(a) Uptake by Enhancing Surface Binding and Facilitating Macropinocytosis.

BACKGROUND: High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB100-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a). METHODS: Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting. RESULTS: The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis. CONCLUSIONS: These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and some antidepressant compounds.

How do DEI initiatives impact STEMM, and why do we still need them?

The number of diversity, equity, and inclusion (DEI) initiatives in science, technology, engineering, mathematics, and medicine (STEMM) have grown over the last few years. We asked several Black scientists what impact they have and why STEMM still needs them. They answer these questions and describe how DEI initiatives should evolve.

Acute and adaptive cardiovascular and metabolic effects of passive heat therapy or high-intensity interval training in patients with severe lower-limb osteoarthritis.

Exercise is painful and difficult to perform for patients with severe lower-limb osteoarthritis; consequently, reduced physical activity contributes to increased cardiometabolic disease risk. The aim of this study was to characterize the acute and adaptive cardiovascular and metabolic effects of two low or no impact therapies in patients with severe lower-limb osteoarthritis: passive heat therapy (Heat) and high-intensity interval training (HIIT) utilizing primarily the unaffected limbs, compared to a control intervention of home-based exercise (Home). Participants completed up to 12 weeks of either Heat (20-30 min immersed in 40°C water followed by ~15-min light resistance exercise), HIIT (6-8 × 60-s intervals on a cross-trainer or arm ergometer at ~90-100% peak V ̇ $$ \dot{V} $$ O2 ) or Home (~15-min light resistance exercise); all 3 sessions/week. Reductions in systolic (12 & 10 mm Hg), diastolic (7 & 4 mm Hg), and mean arterial (8 & 6 mm Hg) blood pressure (BP) were observed following one bout of Heat or HIIT exposure, lasting for the duration of the 20-min monitoring period. Across the interventions (i.e., 12 weeks), resting systolic BP and diastolic BP decreased with Heat (-9 & -4 mm Hg; p < 0.001) and HIIT (-7 & -3 mm Hg; p ≤ 0.011), but not Home (0 & 0 mm Hg; p ≥ 0.785). The systolic and diastolic BP responses to an acute exposure of Heat or HIIT in the first intervention session were moderately correlated with adaptive responses across the intervention (r ≥ 0.54, p ≤ 0.005). Neither intervention improved indices of glycemic control (p = 0.310). In summary, both Heat and HIIT induced potent immediate and adaptive hypotensive effects, and the acute response was moderately predictive of the long-term response.

Evidence for Prepulse Inhibition of Visually Evoked Motor Response in Drosophila melanogaster.

Prepulse inhibition (PPI) is a widely investigated behavior to study the mechanisms of disorders such as anxiety, schizophrenia, and bipolar mania. PPI has been observed across various vertebrate and invertebrate species; however, it has not yet been reported in adult Drosophila melanogaster. In this study, we describe the first detection of PPI of visually evoked locomotor arousal in flies. To validate our findings, we demonstrate that PPI in Drosophila can be partially reverted by the N-methyl D-aspartate (NMDA) receptor antagonist MK-801, known for inducing sensorimotor gating deficits in rodent models. Additionally, we show that the visually evoked response can be inhibited by multiple stimuli presentation, which can also be affected by MK-801. Given the versatility of Drosophila as a model organism for genetic screening and analysis, our results suggest that high-throughput behavioral screenings of adult flies can become a valuable tool for investigating the mechanisms behind PPI.

Childhood Social Isolation as a Predictor of Retinal Neuronal Thickness in Middle Age: A Lifecourse Birth Cohort Study.

OBJECTIVE: We investigated whether childhood social isolation was associated with retinal neural layer changes in adulthood, and whether this association was independent of other childhood or adulthood risk factors, including adult social isolation. METHODS: Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal population-based birth cohort from Aotearoa New Zealand ( n = 1037), born 1972 to 1973 and followed until age 45 years, with 94% of the living cohort still participating. Social isolation was recorded prospectively at ages 5, 7, 9, and 11 years, from teacher and parent report. Retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer thicknesses were measured via optical coherence tomography at age 45 years. RESULTS: Childhood social isolation was associated with thinner average RNFL ( B = -0.739, p = .02), nasal RNFL ( B = -1.118, p = .005), and inferior RNFL ( B = -1.524, p = .007), although only nasal RNFL remained significant after adjustment. These associations were not fully explained by other psychosocial or physical health risk factors in childhood or adulthood, nor were they mediated by adult loneliness or social support. CONCLUSIONS: Childhood social isolation was an independent predictor of RNFL thickness in middle age. Highlighting prospective links between childhood psychosocial adversity and retinal neuronal measures will help to inform future research into the utility of retinal neuronal thickness as a biomarker for neurodegeneration.

Effects of Transient Administration of the NMDA Receptor Antagonist MK-801 in Drosophila melanogaster Activity, Sleep, and Negative Geotaxis.

MK-801, also called dizocilpine, is an N-methyl-D-aspartate (NMDA) receptor antagonist widely used in animal research to model schizophrenia-like phenotypes. Although its effects in rodents are well characterised, little is known about the outcomes of this drug in other organisms. In this study, we characterise the effects of MK-801 on the locomotion, sleep, and negative geotaxis of the fruit fly Drosophila melanogaster. We observed that acute (24 h) and chronic (7 days) administration of MK-801 enhanced negative geotaxis activity in the forced climbing assay for all tested concentrations (0.15 mM, 0.3 mM, and 0.6 mM). Moreover, acute administration, but not chronic, increased the flies' locomotion in a dose-dependent matter. Finally, average sleep duration was not affected by any concentration or administration protocol. Our results indicate that acute MK-801 could be used to model hyperactivity phenotypes in Drosophila melanogaster. Overall, this study provides further evidence that the NMDA receptor system is functionally conserved in flies, suggesting the usefulness of this model to investigate several phenotypes as a complement and replacement of the rodent models within drug discovery.

A simple high-throughput method for automated detection of Drosophila melanogaster light-dependent behaviours.

BACKGROUND: Like most living organisms, the fruit fly Drosophila melanogaster exhibits strong and diverse behavioural reactions to light. Drosophila is a diurnal animal that displays both short- and long-term responses to light, important for, instance, in avoidance and light wavelength preference, regulation of eclosion, courtship, and activity, and provides an important model organism for understanding the regulation of circadian rhythms both at molecular and circuit levels. However, the assessment and comparison of light-based behaviours is still a challenge, mainly due to the lack of a standardised platform to measure behaviour and different protocols created across studies. Here, we describe the Drosophila Interactive System for Controlled Optical manipulations (DISCO), a low-cost, automated, high-throughput device that records the flies' activity using infrared beams while performing LED light manipulations. RESULTS: To demonstrate the effectiveness of this tool and validate its potential as a standard platform, we developed a number of distinct assays, including measuring the locomotor response of flies exposed to sudden darkness (lights-off) stimuli. Both white-eyed and red-eyed wild-type flies exhibit increased activity after the application of stimuli, while no changes can be observed in Fmr1 null allele flies, a model of fragile X syndrome. Next, to demonstrate the use of DISCO in long-term protocols, we monitored the circadian rhythm of the flies for 48 h while performing an alcohol preference test. We show that increased alcohol consumption happens intermittently throughout the day, especially in the dark phases. Finally, we developed a feedback-loop algorithm to implement a place preference test based on the flies' innate aversion to blue light and preference for green light. We show that both white-eyed and red-eyed wild-type flies were able to learn to avoid the blue-illuminated zones. CONCLUSIONS: Our results demonstrate the versatility of DISCO for a range of protocols, indicating that this platform can be used in a variety of ways to study light-dependent behaviours in flies.