Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by the presence of intracellular aggregates of tau protein and neuronal loss leading to cognitive and motor impairment. Occurrence is mostly sporadic, but rare family clusters have been described. Although the etiopathology of PSP is unknown, mutations in the MAPT/tau gene and exposure to environmental toxins can increase the risk of PSP. Here, we used cell models to investigate the potential neurotoxic effects of heavy metals enriched in a highly industrialized region in France with a cluster of sporadic PSP cases. We found that iPSC-derived iNeurons from a MAPT mutation carrier tend to be more sensitive to cell death induced by chromium (Cr) and nickel (Ni) exposure than an isogenic control line. We hypothesize that genetic variations may predispose to neurodegeneration induced by those heavy metals. Furthermore, using an SH-SY5Y neuroblastoma cell line, we showed that both heavy metals induce cell death by an apoptotic mechanism. Interestingly, Cr and Ni treatments increased total and phosphorylated tau levels in both cell types, implicating Cr and Ni exposure in tau pathology. Overall, this study suggests that chromium and nickel could contribute to the pathophysiology of tauopathies such as PSP by promoting tau accumulation and neuronal cell death

Social Competence Treatment after Traumatic Brain Injury: A Multicenter, Randomized, Controlled Trial of Interactive Group Treatment versus Non-Interactive Treatment

Objective To evaluate the effectiveness of a replicable group treatment program for improving social competence after traumatic brain injury (TBI). Design Multicenter randomized controlled trial comparing two methods of conducting a social competency skills program, an interactive group format versus a classroom lecture. Setting Community and Veteran rehabilitation centers. Participants 179 civilian, military, and veteran adults with TBI and social competence difficulties, at least 6 months post-injury. Experimental Intervention Thirteen weekly group interactive sessions (1.5 hours) with structured and facilitated group interactions to improve social competence. Alternative (Control) Intervention Thirteen traditional classroom sessions using the same curriculum with brief supplemental individual sessions but without structured group interaction. Primary Outcome Measure Profile of Pragmatic Impairment in Communication (PPIC), an objective behavioral rating of social communication impairments following TBI. Secondary Outcomes LaTrobe Communication Questionnaire (LCQ), Goal Attainment Scale (GAS), Satisfaction with Life Scale (SWLS), Post-Traumatic Stress Disorder Checklist – (PCL-C), Brief Symptom Inventory 18 (BSI-18), Scale of Perceived Social Self Efficacy (PSSE). Results Social competence goals (GAS) were achieved and maintained for most participants regardless of treatment method. Significant improvements in the primary outcome (PPIC) and two of the secondary outcomes (LCQ and BSI) were seen immediately post-treatment and at 3 months post-treatment in the AT arm only, however these improvements were not significantly different between the GIST and AT arms. Similar trends were observed for PSSE and PCL-C. Conclusions Social competence skills improved for persons with TBI in both treatment conditions. The group interactive format was not found to be a superior method of treatment delivery in this study

Sex differences in clinical characteristics and outcomes in patients undergoing heart transplantation

Aims: Whether sex affects selection for and outcomes after heart transplantation (HTx) remains unclear. We aimed to show sex differences in pre‐transplant characteristics and outcomes after HTx. Methods and results: From 1995 to 2019, 49 200 HTx recipients were prospectively enrolled in the Organ Procurement and Transplantation Network. Logistic regression models were used to evaluate clinical characteristics by sex. Multivariable Cox regression models were fitted to assess sex differences in all‐cause mortality, cardiovascular mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. In 49 200 patients (median age 55 years, interquartile range 46–62; 24.6% women), 49 732 events occurred during a median follow‐up of 8.1 years. Men were older than women, had more often ischaemic cardiomyopathy (odds ratio [OR] 3.26, 95% confidence interval [CI] 3.11–3.42; P < 0.001), and a higher burden of cardiovascular risk factors, whereas women had less malignancies (OR 0.47, CI 0.44–0.51; P < 0.001). Men were more often treated in intensive care unit (OR 1.24, CI 1.12–1.37; P < 0.001) with a higher need for ventilatory (OR 1.24, CI 1.17–1.32; P < 0.001) or VAD (OR 1.53, CI 1.45–1.63; P < 0.001) support. After multivariable adjustment, men had a higher risk for CAV (hazard ratio [HR] 1.21, CI 1.13–1.29; P < 0.001) and malignancy (HR 1.80, CI 1.62–2.00; P < 0.001). There were no differences in all‐cause mortality, cardiovascular mortality, and graft failure between sexes. Conclusions: In this US transplant registry, men and women differed in pre‐transplant characteristics. Male sex was independently associated with incident CAV and malignancy even after multivariable adjustment. Our results underline the need for better personalized post‐HTx management and care

Increase in NDM-1 and NDM-1/OXA-48-producing Klebsiella pneumoniae in Germany associated with the war in Ukraine, 2022

In 2022, German surveillance systems observed rapidly increasing numbers of NDM-1- and NDM-1/OXA-48-producing Klebsiella pneumoniae, which may in part reflect recurring pre-pandemic trends. Among these cases, however, a presence in Ukraine before diagnosis was frequently reported. Whole genome sequencing of 200 isolates showed a high prevalence of sequence types ST147, ST307, ST395 and ST23, including clusters corresponding to clonal dissemination and suggesting onward transmission in Germany. Screening and isolation of patients from Ukraine may help avoid onward transmission.Peer Reviewe

Tentative detection of the circumgalactic medium of the isolated low-mass dwarf galaxy WLM

We report a tentative detection of the circumgalactic medium (CGM) of Wolf–Lundmark–Melotte (WLM), an isolated, low-mass (logM*/M⊙ ≈ 7.6), dwarf irregular galaxy in the Local Group (LG). We analyse an HST/COS archival spectrum of a quasar sightline (PHL2525), which is 45 kpc (0.5 virial radius) from WLM and close to the Magellanic Stream (MS). Along this sightline, two ion absorbers are detected in Si II, Si III, Si IV, C II, and C IV at velocities of ∼−220 km s⁻¹ (Component v-220) and ∼−150 km s⁻¹ (Component v-150). To identify their origins, we study the position–velocity alignment of the components with WLM and the nearby MS. Near the magellanic longitude of PHL2525, the MS-related neutral and ionized gas moves at ≲−190 km s⁻¹, suggesting an MS origin for Component v-220, but not for Component v-150. Because PHL2525 passes near WLM and Component v-150 is close to WLM’s systemic velocity (∼−132 km s⁻¹), it is likely that Component v-150 arises from the galaxy’s CGM. This results in a total Si mass in WLM’s CGM of M^(CGM)_(Si)∼(0.2−1.0)×10⁵ M⊙ using assumption from other COS dwarf studies. Comparing M^(CGM)_(Si) to the total Si mass synthesized in WLM over its lifetime (∼1.3 × 10⁵ M⊙), we find ∼3 per cent is locked in stars, ∼6 per cent in the ISM, ∼15–77 per cent in the CGM, and the rest (∼14–76 per cent) is likely lost beyond the virial radius. Our finding resonates with other COS dwarf galaxy studies and theoretical predictions that low-mass galaxies can easily lose metals into their CGM due to stellar feedback and shallow gravitational potential

Weekly chemotherapy with radiation versus high‐dose cisplatin with radiation as organ preservation for patients with HPV‐positive and HPV‐negative locally advanced squamous cell carcinoma of the oropharynx

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106948/1/hed23339.pd

Photoexcitation of tumor-targeted corroles induces singlet oxygen-mediated augmentation of cytotoxicity

The tumor-targeted corrole particle, HerGa, displays preferential toxicity to tumors in vivo and can be tracked via fluorescence for simultaneous detection, imaging, and treatment. We have recently uncovered an additional feature of HerGa in that its cytotoxicity is enhanced by light irradiation. In the present study, we have elucidated the cellular mechanisms for HerGa photoexcitation-mediated cell damage using fluorescence optical imaging. In particular, we found that light irradiation of HerGa produces singlet oxygen, causing mitochondrial damage and cytochrome c release, thus promoting apoptotic cell death. An understanding of the mechanisms of cell death induced by HerGa, particularly under conditions of light-mediated excitation, may direct future efforts in further customizing this nanoparticle for additional therapeutic applications and enhanced potency

Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics

Resistance to anti-tumor therapeutics is an important clinical problem. Tumor-targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases. Targeting such resistance could improve tumor abatement and patient survival. A growing number of such tumors are characterized by prominent expression of the human epidermal growth factor receptor 3 (HER3) on the cell surface. This study presents a “Trojan-Horse” approach to combating these tumors by using a receptor-targeted biocarrier that exploits the HER3 cell surface protein as a portal to sneak therapeutics into tumor cells by mimicking an essential ligand. The biocarrier used here combines several functions within a single fusion protein for mediating targeted cell penetration and non-covalent self-assembly with therapeutic cargo, forming HER3-homing nanobiologics. Importantly, we demonstrate here that these nanobiologics are therapeutically effective in several scenarios of resistance to clinically approved targeted inhibitors of the human EGF receptor family. We also show that such inhibitors heighten efficacy of our nanobiologics on naïve tumors by augmenting HER3 expression. This approach takes advantage of a current clinical problem (i.e. resistance to growth factor inhibition) and uses it to make tumors more susceptible to HER3 nanobiologic treatment. Moreover, we demonstrate a novel approach in addressing drug resistance by taking inhibitors against which resistance arises and re-introducing these as adjuvants, sensitizing tumors to the HER3 nanobiologics described here