Sex differences in treatment effect in neuroprotectant trials for acute ischemic stroke: A systematic review.

BACKGROUND: Pre-clinical data suggest sex differences in mechanisms of cerebral ischemic injury. This might result in differential outcomes of putative neuroprotectants by sex, though little systematic data is available to assess this. METHODS: We performed a systematic review of multicenter randomized controlled trials published from January 1980-June 2022 enrolling >100 subjects and testing neuroprotectants in acute ischemic stroke (AIS). For each trial, reported treatment effect by sex was extracted. When published results by sex were not available, we contacted individual authors to attempt to retrieve these data. RESULTS: We identified 59 publications reporting 64 trials that met inclusion criteria. Of these, data on treatment effect by sex were published for 14/64 trials. Unpublished data for an additional 5 trials were obtained from trial investigators (19/64, or 29.7%). Two trials (one testing uric acid and one dexborneol) reported treatment benefit in women but not men. Pooled analysis of six trials of tirilazad reported worse treatment outcomes in women and no effect in men. No clear difference was apparent in the other trials. CONCLUSIONS: Most trials did not report treatment effect by sex. Of those that did, there was little evidence of systematic sex differences in treatment response.

Vessel wall imaging in the diagnosis of antiphospholipid syndrome presenting as Moyamoya syndrome-A case report.

Objectives: We describe a case of anti-phospholipid syndrome (APLS) vasculopathy presenting with Moyamoya syndrome (MMS) and show the associated intracranial vessel wall MRI (VWI) findings. Methods: A 37-year-old-woman presented with acute onset dizziness and left-sided weakness. Neurologic exam revealed a left facial droop and left hemiparesis. She underwent a comprehensive laboratory work-up for stroke. Neuroimaging included a CT head, CT angiogram, VWI, and digital subtraction angiography. Results: Work-up revealed a triple-positive APLS antibody profile. CT of the head showed an acute right basal ganglia infarction and right frontal subarachnoid hemorrhage. CT angiogram revealed severe stenosis of the right internal carotid artery terminus in a Moyamoya pattern. Intracranial VWI showed long-segment concentric vessel wall thickening and homogeneous vessel wall enhancement and T2-hyperintense wall edema of the stenotic right ICA terminus, M1 middle cerebral artery, and A1 anterior cerebral artery. She was treated with long-term anticoagulation with warfarin and a right superficial temporal artery to middle cerebral artery bypass. Discussion: We present intracranial VWI features of vessel wall pathology in a patient with primary APLS presenting with MMS.

Common activities and predictive gene signature identified for genetic hypomorphs of TP53.

Missense mutations that inactivate p53 occur commonly in cancer, and germline mutations in TP53 cause Li Fraumeni syndrome, which is associated with early-onset cancer. In addition, there are over two hundred germline missense variants of p53 that remain uncharacterized. In some cases, these germline variants have been shown to encode lesser-functioning, or hypomorphic, p53 protein, and these alleles are associated with increased cancer risk in humans and mouse models. However, most hypomorphic p53 variants remain un- or mis-classified in clinical genetics databases. There thus exists a significant need to better understand the behavior of p53 hypomorphs and to develop a functional assay that can distinguish hypomorphs from wild-type p53 or benign variants. We report the surprising finding that two different African-centric genetic hypomorphs of p53 that occur in distinct functional domains of the protein share common activities. Specifically, the Pro47Ser variant, located in the transactivation domain, and the Tyr107His variant, located in the DNA binding domain, both share increased propensity to misfold into a conformation specific for mutant, misfolded p53. Additionally, cells and tissues containing these hypomorphic variants show increased NF-κB activity. We identify a common gene expression signature from unstressed lymphocyte cell lines that is shared between multiple germline hypomorphic variants of TP53, and which successfully distinguishes wild-type p53 and a benign variant from lesser-functioning hypomorphic p53 variants. Our findings will allow us to better understand the contribution of p53 hypomorphs to disease risk and should help better inform cancer risk in the carriers of p53 variants.

Targeting ErbB3 and Cellular NADPH/NADP+ Abundance Sensitizes Cutaneous Melanomas to Ferroptosis Inducers.

Melanoma is a serious health challenge. Ferroptosis is a regulated form of oxidative cell death that shows varied efficacy in melanoma. We aimed to better understand the molecular basis for this differential ferroptosis sensitivity. We find that elevated expression of ErbB3 (V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homologue 3) associates with ferroptosis resistance and that ErbB3 knockdown sensitizes to ferroptosis inducers. ErbB3 depletion also promotes a marked reduction in the cellular ratio of GSH/GSSG (reduced/oxidized glutathione) and that of NADPH/NADP+ (reduced/oxidized nicotinamide adenine dinucleotide phosphate), together with an increase in the abundance of the lipid peroxidation product malondialdehyde (MDA). We identify several small molecule inhibitors targeting ErbB3 signaling pathways that also reduce the NADPH/NADP+ and GSH/GSSG ratios, concomitantly sensitizing the melanomas to ferroptosis activators. These findings point to a previously unrecognized role of ErbB3 in ferroptosis sensitivity and provide new insight into pathways that regulate this cell death process.

Cerebral Infarction due to Severe ADAMTS-13 Deficiency with Normal Hematological Parameters: A Cause of Cryptogenic Stroke.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy resulting from an inherited or acquired severe deficiency in a disintegrin and metalloproteinase called ADAMTS-13. Acquired or immune TTP is classically described as a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal insufficiency and neurological symptoms. Thrombotic thrombocytopenic purpura has been linked to stroke with the presence of hematologic abnormalities but whether or not severe ADAMTS-13 deficiency can cause stroke without hematological abnormalities is unknown. MATERIALS AND METHODS: As part of routine clinical care, we identified four cases of recurrent stroke attributed to severe deficiency of ADAMTS-13. We also conducted a search of a centralized electronic health record database including all inpatients and outpatient charts at a single academic medical center over the last ten years in an attempt to identify additional cases. RESULTS: Here we present four cases of stroke and severe ADAMTS-13 deficiency where stroke episodes occurred without microangiopathic hemolytic anemia or severe thrombocytopenia. These cases show the need to consider severe ADAMTS-13 deficiency in the setting of recurrent cryptogenic stroke in young patients. CONCLUSIONS AND RELEVANCE: TTP directed therapies may be considered for patients with recurrent stroke who have extremely low ADAMTS-13 levels, even when platelet and hemoglobin values are normal.

P53 regulates cellular redox state, ferroptosis and metabolism.

The tumor protein P53 (TP53, or p53) has complex and at times seemingly contradictory roles in the regulation of metabolism and ferroptosis sensitivity. We find that the actions of p53 influence the redox state, which can trigger changes in redox-sensitive proteins, thereby modifying metabolic processes and response to ferroptosis.

Key Components of the Batterer Intervention Program Process: An Analysis of Observational Data From Two Community-Based BIPs.

Qualitative research on batterer intervention programs (BIPs) has primarily consisted of interview-based studies of clients and facilitators. To date, no research has utilized observational data to understand how BIPs "work," or the processes occurring in BIPs that promote prosocial behavioral change. Forty-four observations of BIP group sessions were conducted. Two key processes were found: "facilitator processes" (e.g., managing group dynamics and engaging clients in learning) and "client processes" (e.g., mutual aid, help-seeking, and support). More observational research on BIPs is needed to uncover the full range of processes occurring during BIPs and that can link group processes to client outcomes.

HSP70 inhibition blocks adaptive resistance and synergizes with MEK inhibition for the treatment of NRAS-mutant melanoma.

NRAS-mutant melanoma is currently a challenge to treat. This is due to an absence of inhibitors directed against mutant NRAS, along with adaptive and acquired resistance of this tumor type to inhibitors in the MAPK pathway. Inhibitors to MEK (mitogen-activated protein kinase kinase) have shown some promise for NRAS-mutant melanoma. In this work we explored the use of MEK inhibitors for NRAS-mutant melanoma. At the same time we investigated the impact of the brain microenvironment, specifically astrocytes, on the response of a melanoma brain metastatic cell line to MEK inhibition. These parallel avenues led to the surprising finding that astrocytes enhance the sensitivity of melanoma tumors to MEK inhibitors (MEKi). We show that MEKi cause an upregulation of the transcription factor ID3, which confers resistance. This upregulation of ID3 is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEK inhibitors, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEK inhibitors against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma. SIGNIFICANCE: MEK inhibitors are currently used for NRAS-mutant melanoma, but have shown modest efficacy as single agents. This research shows a synergistic effect of combining HSP70 inhibitors with MEK inhibitors for the treatment of NRAS mutant melanoma.

The Challenges of Working With Men Who Perpetrate Partner Violence: Perspectives and Observations of Experts Who Work With Batterer Intervention Programs.

Batterer intervention programs (BIPs) constitute the primary treatment for perpetrators of intimate partner violence (IPV). Systematic evaluations of BIPs, however, have yielded modest results in terms of these programs' ability to reduce perpetration. Descriptive studies, which can provide information on the contexts and process associated with BIPs, can provide insights into the underlying mechanisms that might promote change among BIP clients, and as such are important to improving efficacy measures for BIPs. To date, however, limited research exists on what challenges BIPs encounter in working with clients, and how those challenges present barriers to behavioral change among perpetrators at the intervention level. As part of a 2-year ethnographic study, we conducted 36 individual semistructured interviews with professionals working with BIPs. We identified six themes related to challenges to promoting behavioral change among men who perpetrate violence: (a) social acceptance of IPV, (b) hypermasculine attitudes, (c) emotional problems, (d) childhood exposure to violence, (e) co-morbid mental health issues, and (f) denial, minimization, and blame. Our results have implications for thinking about some of the contextual factors that may impede BIPs ability to produce desired outcomes and for identifying areas in which programs can be tailored to improve the overall client experience. Our results also point to the need for a more coordinated community response to IPV, and in particular to helping provide resources that support BIPs sustained, safe, and as effective as possible work.

Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser.

The Pro47Ser variant of p53 (S47) exists in African-descent populations and is associated with increased cancer risk in humans and mice. Due to impaired repression of the cystine importer Slc7a11, S47 cells show increased glutathione (GSH) accumulation compared to cells with wild -type p53. We show that mice containing the S47 variant display increased mTOR activity and oxidative metabolism, as well as larger size, improved metabolic efficiency, and signs of superior fitness. Mechanistically, we show that mTOR and its positive regulator Rheb display increased association in S47 cells; this is due to an altered redox state of GAPDH in S47 cells that inhibits its ability to bind and sequester Rheb. Compounds that decrease glutathione normalize GAPDH-Rheb complexes and mTOR activity in S47 cells. This study reveals a novel layer of regulation of mTOR by p53, and raises the possibility that this variant may have been selected for in early Africa.

Functional interplay among thiol-based redox signaling, metabolism, and ferroptosis unveiled by a genetic variant of TP53.

The p53 tumor suppressor protein is a transcription factor and master stress response mediator, and it is subject to reduction-oxidation (redox)-dependent regulation. The P47S variant of TP53, which exists primarily in African-descent populations, associates with an elevated abundance of low molecular weight (LMW) thiols, including glutathione (GSH) and coenzyme A (CoA). Here we show that S47 and P47 cells exhibit distinct metabolic profiles, controlled by their different redox states and expression of Activating Transcription Factor-4 (ATF4). We find that S47 cells exhibit decreased catabolic glycolysis but increased use of the pentose phosphate pathway (PPP), and an enhanced abundance of the antioxidant, NADPH. We identify ATF4 as differentially expressed in P47 and S47 cells and show that ATF4 can reverse the redox status and rescue metabolism of S47 cells, as well as increase sensitivity to ferroptosis. This adaptive metabolic switch is rapid, reversible, and accompanied by thiol-mediated changes in the structures and activities of key glycolytic signaling pathway proteins, including GAPDH and G6PD. The results presented here unveil the important functional interplay among pathways regulating thiol-redox status, metabolic adaptation, and cellular responses to oxidative stress.

A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors.

The protein chaperone HSP70 is overexpressed in many cancers including colorectal cancer, where overexpression is associated with poor survival. We report here the creation of a uniquely acting HSP70 inhibitor (HSP70i) that targets multiple compartments in the cancer cell, including mitochondria. This inhibitor was mitochondria toxic and cytotoxic to colorectal cancer cells, but not to normal colon epithelial cells. Inhibition of HSP70 was efficacious as a single agent in primary and metastatic models of colorectal cancer and enabled identification of novel mitochondrial client proteins for HSP70. In a syngeneic colorectal cancer model, the inhibitor increased immune cell recruitment into tumors. Cells treated with the inhibitor secreted danger-associated molecular patterns (DAMP), including ATP and HMGB1, and functioned effectively as a tumor vaccine. Interestingly, the unique properties of this HSP70i in the disruption of mitochondrial function and the inhibition of proteostasis both contributed to DAMP release. This HSP70i constitutes a promising therapeutic opportunity in colorectal cancer and may exhibit antitumor activity against other tumor types. SIGNIFICANCE: These findings describe a novel HSP70i that disrupts mitochondrial proteostasis, demonstrating single-agent efficacy that induces immunogenic cell death in treated tumors.

Author Correction: African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin.

A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07-2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa.

Human Services Utilization Among Male IPV Perpetrators: Relationship to Timing and Completion of Batterer Intervention Programs.

Limited information exists on the extent to which male perpetrators of Intimate Partner Violence (IPV) are engaged in the use of human services for co-occuringpsychosocial and health issues. The current analysis uses administrative data from one batterer intervention program (BIP) and data from the local Department of Human Services to explore perpetrators' engagement with human services, and the relationship of that use to timing and completion of the BIP. Data for 330 adult male clients referred to the participating BIP from 2010 to 2015 were collected. A majority (63%) had engaged in at least one human service program. The most common kind of service was mental health (46%). The most specific service engagement was child welfare as a parent (41%). Engagement largely concluded prior to beginning the BIP. BIP completers had less service use overall. Future work should explore how these services could be utilized to improve the success of BIPs and reduce perpetration.

Disability after minor stroke and TIA: A secondary analysis of the SOCRATES trial.

OBJECTIVE: To examine factors associated with disability following TIA and minor stroke, including poststroke complications such as stroke recurrence, major bleeding, and other adverse medical events. METHODS: The SOCRATES trial randomized patients with TIA/minor stroke (NIH Stroke Scale [NIHSS] score ≤5) within 24 hours of onset. We performed a post hoc analysis of factors associated with disability (modified Rankin Scale [mRS] score >1). TIA and minor stroke were analyzed separately. Patients with premorbid mRS >0 were excluded. RESULTS: At 90 days, 687/3,663 (19%) patients with stroke were disabled; for TIA, 122/2,384 (5%) were disabled. In multivariate analyses, age, diabetes, and NIHSS were associated with disability in the stroke cohort, and age with disability in the TIA cohort. Postrandomization events (recurrent stroke, myocardial infarction, major bleeding, serious adverse events) were strongly associated with disability in both cohorts (stroke cohort: odds ratio [OR] 5.6, 95% confidence interval [CI] 4.5-6.9; TIA cohort: OR 14.8, 95% CI 9.9-22.0). Of the TIA patients who ended up disabled, 65% experienced a postrandomization event; for stroke patients who ended up disabled, 39% had a postrandomization event. Disability increased linearly with NIHSS score (p < 0.0001) and was greater in those with limb weakness (p < 0.0001). CONCLUSIONS: After TIA and minor stroke, subsequent stroke and medical complications are strongly associated with disability. In addition, even within a low range of baseline scores, the NIHSS is a powerful predictor of disability in minor stroke patients, with items scoring limb weakness particularly associated with subsequent disability.

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53.

A population-restricted single-nucleotide coding region polymorphism (SNP) at codon 47 exists in the human TP53 gene (P47S, hereafter P47 and S47). In studies aimed at identifying functional differences between these variants, we found that the African-specific S47 variant associates with an impaired response to agents that induce the oxidative stress-dependent, nonapoptotic cell death process of ferroptosis. This phenotype is manifested as a greater resistance to glutamate-induced cytotoxicity in cultured cells as well as increased carbon tetrachloride-mediated liver damage in a mouse model. The differential ferroptotic responses associate with intracellular antioxidant differences between P47 and S47 cells, including elevated abundance of the low molecular weight thiols coenzyme A (CoA) and glutathione in S47 cells. Importantly, the disparate ferroptosis phenotypes related to the P47S polymorphism are reversible. Exogenous administration of CoA provides protection against ferroptosis in cultured mouse and human cells, as well as in a mouse model. The combined data support a positive role for p53 in ferroptosis and identify CoA as a regulator of this cell death process. Together, these findings provide mechanistic insight linking redox regulation of p53 to small molecule antioxidants and stress signaling pathways. They also identify potential therapeutic approaches to redox-related pathologies.

Lyme myelopathy: Case report and literature review of a rare but treatable disorder.

The differential diagnosis for transverse myelitis is extensive, and the prognosis is highly variable depending on the etiology. We describe a rare case of a 56-year-old previously healthy male who presented with thoracic paresthesias and hyperesthesias involving the T6-11 dermatomes several weeks after a febrile illness. A thoracic MRI demonstrated a T7-10 transverse myelitis, and an exhaustive evaluation revealed neuroborreliosis. His symptoms improved significantly after an initial steroid course and 21 day course of ceftriaxone. We review neuroborreliosis and summarize the features of 23 previously reported cases of Lyme myelopathy. Although Lyme myelopathy is rare, including Lyme in the differential diagnosis of an acute transverse myelitis work up is important in endemic regions, as it is a potentially reversible disorder with a generally good prognosis when appropriately treated with antibiotics.

Male Intimate Partner Violence Perpetrators' Perceptions of the Positives and Negatives of Peer Interactions in Group Batterer Intervention Programs.

Seventy-six adult male perpetrators of intimate partner violence enrolled in a batterer intervention program (BIP) were interviewed on their perspectives of the intra-BIP group peer interactions. A majority of participants endorsed positives aspects of working with peers in the group context. Only one negative aspect arose, namely, other group members who disrupted the BIP process in some way. More importantly, a minority of participants expressed indifference toward the group process. This study has implications for training of BIP facilitators and for future research on BIPs that helps to tailor the approaches these groups use to maximize client engagement.

The Operational Challenges for Batterer Intervention Programs: Results From a 2-Year Study.

Batterers intervention programs (BIPs) constitute a primary intervention for perpetrators of intimate partner violence (IPV). There is little understanding as to what operational, or program-level, challenges BIPs face that can impede their effectiveness and adherence to state standards. As part of a 2-year ethnographic study, we conducted 36 individual semistructured interviews with professionals working with BIPs and identified five themes related to program-level challenges for BIPs: (a) information barriers, (b) safety issues, (c) facilitator retention and training, (d) the need for monitoring, and (e) funding constraints. We conclude that continued work needs to be done at both the state and local level, and in coordination with community judicial, mental health, human services, and other agencies to help provide resources that support BIPs in sustained, safe, and as effective as possible work.