Granzyme F: Exhaustion Marker and Modulator of Chimeric Antigen Receptor T Cell-Mediated Cytotoxicity.

Granzymes are a family of proteases used by CD8 T cells to mediate cytotoxicity and other less-defined activities. The substrate and mechanism of action of many granzymes are unknown, although they diverge among the family members. In this study, we show that mouse CD8+ tumor-infiltrating lymphocytes (TILs) express a unique array of granzymes relative to CD8 T cells outside the tumor microenvironment in multiple tumor models. Granzyme F was one of the most highly upregulated genes in TILs and was exclusively detected in PD1/TIM3 double-positive CD8 TILs. To determine the function of granzyme F and to improve the cytotoxic response to leukemia, we constructed chimeric Ag receptor T cells to overexpress a single granzyme, granzyme F or the better-characterized granzyme A or B. Using these doubly recombinant T cells, we demonstrated that granzyme F expression improved T cell-mediated cytotoxicity against target leukemia cells and induced a form of cell death other than chimeric Ag receptor T cells expressing only endogenous granzymes or exogenous granzyme A or B. However, increasing expression of granzyme F also had a detrimental impact on the viability of the host T cells, decreasing their persistence in circulation in vivo. These results suggest a unique role for granzyme F as a marker of terminally differentiated CD8 T cells with increased cytotoxicity, but also increased self-directed cytotoxicity, suggesting a potential mechanism for the end of the terminal exhaustion pathway.

Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila.

BACKGROUND: Many common diseases exhibit uncontrolled mTOR signaling, prompting considerable interest in the therapeutic potential of mTOR inhibitors, such as rapamycin, to treat a range of conditions, including cancer, aging-related pathologies, and neurological disorders. Despite encouraging preclinical results, the success of mTOR interventions in the clinic has been limited by off-target side effects and dose-limiting toxicities. Improving clinical efficacy and mitigating side effects require a better understanding of the influence of key clinical factors, such as sex, tissue, and genomic background, on the outcomes of mTOR-targeting therapies. RESULTS: We assayed gene expression with and without rapamycin exposure across three distinct body parts (head, thorax, abdomen) of D. melanogaster flies, bearing either their native melanogaster mitochondrial genome or the mitochondrial genome from a related species, D. simulans. The fully factorial RNA-seq study design revealed a large number of genes that responded to the rapamycin treatment in a sex-dependent and tissue-dependent manner, and relatively few genes with the transcriptional response to rapamycin affected by the mitochondrial background. Reanalysis of an earlier study confirmed that mitochondria can have a temporal influence on rapamycin response. CONCLUSIONS: We found significant and wide-ranging effects of sex and body part, alongside a subtle, potentially time-dependent, influence of mitochondria on the transcriptional response to rapamycin. Our findings suggest a number of pathways that could be crucial for predicting potential side effects of mTOR inhibition in a particular sex or tissue. Further studies of the temporal response to rapamycin are necessary to elucidate the effects of the mitochondrial background on mTOR and its inhibition.

Role of IFN-α in Rheumatoid Arthritis.

PURPOSE OF REVIEW: Type 1 interferons (IFN-I) are of increasing interest across a wide range of autoimmune rheumatic diseases. Historically, research into their role in rheumatoid arthritis (RA) has been relatively neglected, but recent work continues to highlight a potential contribution to RA pathophysiology. RECENT FINDINGS: We emphasise the importance of disease stage when examining IFN-I in RA and provide an overview on how IFN-I may have a direct role on a variety of relevant cellular functions. We explore how clinical trajectory may be influenced by increased IFN-I signalling, and also, the limitations of scores composed of interferon response genes. Relevant environmental triggers and inheritable RA genetic risk relating to IFN-I signalling are explored with emphasis on intriguing data potentially linking IFN-I exposure, epigenetic changes, and disease relevant processes. Whilst these data cumulatively illustrate a likely role for IFN-I in RA, they also highlight the knowledge gaps, particularly in populations at risk for RA, and suggest directions for future research to both better understand IFN-I biology and inform targeted therapeutic strategies.

Activation of the aryl hydrocarbon receptor via indole derivatives is a common feature in skin bacterial isolates.

AIMS: The aryl hydrocarbon receptor (AhR) is a ligand-activated receptor implicated in many inflammatory disorders. The skin microbiota plays a crucial role in maintaining epidermal barrier integrity and is thought to modulate skin homeostasis partly through the production of AhR ligands including metabolites of microbial tryptophan metabolism such as indole derivatives. Here, we report the skin microbiota that activate AhR and their unique tryptophan metabolite profiles. METHODS AND RESULTS: Of the bacteria isolated from healthy human skin and screened for the ability to metabolise tryptophan (18 species, five genera), 14 were positive. The tryptophan metabolites of 10 positive and two negative bacteria were then characterised using liquid chromatography-mass spectrometry. Whole genome sequencing confirmed the presence of key genes involved in the indole-3-pyruvic acid pathway within the genomes of indole-3-acetaldehyde, indole-3-acetic acid, and indole-3-aldehyde-producing organisms. A cell-based luciferase reporter gene assay identified functional agonist activity against human AhR in the culture supernatants of 12 of the 18 species tested. High indole derivative-producing organisms induced potent AhR activation. CONCLUSIONS: These data demonstrate the relationship between skin microbiota, tryptophan metabolites, and AhR activation.

Breaking bad news: an active learning method for medical students.

BACKGROUND: Breaking bad news is one of the most difficult aspects of communication in medicine. The objective of this study was to assess the relevance of a novel active learning course on breaking bad news for fifth-year students. METHODS: Students were divided into two groups: Group 1, the intervention group, participated in a multidisciplinary formative discussion workshop on breaking bad news with videos, discussions with a pluri-professional team, and concluding with the development of a guide on good practice in breaking bad news through collective intelligence; Group 2, the control group, received no additional training besides conventional university course. The relevance of discussion-group-based active training was assessed in a summative objective structured clinical examination (OSCE) station particularly through the students' communication skills. RESULTS: Thirty-one students were included: 17 in Group 1 and 14 in Group 2. The mean (range) score in the OSCE was significantly higher in Group 1 than in Group 2 (10.49 out of 15 (7; 13) vs. 7.80 (4.75; 12.5), respectively; p = 0.0007). The proportion of students assessed by the evaluator to have received additional training in breaking bad news was 88.2% (15 of the 17) in Group 1 and 21.4% (3 of the 14) in Group 2 (p = 0.001). The intergroup differences in the Rosenberg Self-Esteem Scale and Jefferson Scale of Empathy scores were not significant, and both scores were not correlated with the students' self-assessed score for success in the OSCE. CONCLUSION: Compared to the conventional course, this new active learning method for breaking bad news was associated with a significantly higher score in a summative OSCE. A longer-term validation study is needed to confirm these exploratory data.

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming.

OBJECTIVES: An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action. METHODS: In a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes. RESULTS: We reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α). CONCLUSIONS: Our data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.

Outcomes during delivery hospitalisations with inflammatory bowel disease.

OBJECTIVE: To characterise inflammatory bowel disease (IBD) trends and associated risk during delivery hospitalisations. DESIGN: Cross-sectional. SETTING: US delivery hospitalisations. POPULATION: Delivery hospitalisations in the 2000-2018 National Inpatient Sample. METHODS: This study analysed a nationally representative hospital discharge database based on the presence of IBD. Temporal trends in IBD were analysed using joinpoint regression to estimate the average annual percent change (AAPC). IBD severity was characterised by the presence of diagnoses such as penetrating and stricturing disease and history of bowel resection. Risks for adverse outcomes were analysed based on presence of IBD. Poisson regression models were performed with unadjusted and adjusted risk ratios (aRR) as measures of effect. MAIN OUTCOME MEASURE: Prevalence of IBD and associated adverse outcomes. RESULTS: Of 73 109 790 delivery hospitalisations, 89 965 had a diagnosis of IBD. IBD rose from 0.06% in 2000 to 0.21% in 2018 (AAPC 7.3%, 95% CI 6.7-7.9%). Among deliveries with IBD, IBD severity diagnoses increased from 4.1% to 8.1% from 2000 to 2018. In adjusted analysis, IBD was associated with increased risk for preterm delivery (aRR 1.50, 95% CI 1.47-1.53), severe maternal morbidity (aRR 1.93, 95% CI 1.83-2.04), venous thrombo-embolism (aRR 2.76, 95% CI 2.39-3.18) and surgical injury during caesarean delivery hospitalisation (aRR 5.03, 95% CI 4.76-5.31). In the presence of a severe IBD diagnosis, risk was further increased for all adverse outcomes. CONCLUSION: IBD is increasing in the obstetric population and is associated with adverse outcomes. Risk is increased in the presence of a severe IBD diagnosis. TWEETABLE ABSTRACT: Deliveries among women with inflammatory bowel disease are increasing. Disease severity is associated with adverse outcomes.

Increasing Nursing Student Success With Early Individual Remediation.

ABSTRACT: With the implementation of five remediation strategies immediately after the first failed exam in a pharmacology course, this quality improvement study demonstrated an increase in retention of at-risk associate degree nursing students. Unit exam scores and course failure rates were measured before and after implementation. Twelve of 14 students who completed the remediation demonstrated a statistically significant increase in scores from the first failed exam to the last exam taken. The mean increase was 17.3 percentage points (p < .0001, 95 percent confidence interval [13.3, 20.9]). Cohen's d, which equaled 0.604, indicated a significant increase in course pass rates.

Barriers to and Facilitators of Using mHealth Technology Among African-Americans Living with Hypertension.

MHealth provides a new way of promoting hypertension self-management behaviors. However, the acceptance, feasibility, and effectiveness of interventions incorporating mHealth technology have been understudied in African-Americans with hypertension. This study aimed to explore participants' (n = 30) experiences using a community and technology-based intervention to self-manage their hypertension (COACHMAN). Focus groups were conducted with African-Americans living with hypertension. Focus groups were audio-recorded, and the data were transcribed verbatim and analyzed qualitatively using thematic analysis. Regarding the use of mHealth-enabled self-management hypertension interventions to support hypertension control among African-Americans, the thematic analysis produced the following five barrier themes: (a) lack of knowledge regarding how to use technology, (b) resistance to learning new technology, (c) lack of access to technology, (d) privacy and security concerns, and (e) issues with the medication management support features. Facilitator themes that emerged from the thematic analysis were all related to the intervention components, which were: (a) reminders, (b) rewards, and (c) education modules. This study focused on mHealth barriers and facilitators as described by African-Americans living with hypertension. Results provide a starting point for developing a mHealth intervention for African-Americans that incorporates a self-management program.

Mitochondrial genotype alters the impact of rapamycin on the transcriptional response to nutrients in Drosophila.

BACKGROUND: In addition to their well characterized role in cellular energy production, new evidence has revealed the involvement of mitochondria in diverse signaling pathways that regulate a broad array of cellular functions. The mitochondrial genome (mtDNA) encodes essential components of the oxidative phosphorylation (OXPHOS) pathway whose expression must be coordinated with the components transcribed from the nuclear genome. Mitochondrial dysfunction is associated with disorders including cancer and neurodegenerative diseases, yet the role of the complex interactions between the mitochondrial and nuclear genomes are poorly understood. RESULTS: Using a Drosophila model in which alternative mtDNAs are present on a common nuclear background, we studied the effects of this altered mitonuclear communication on the transcriptomic response to altered nutrient status. Adult flies with the 'native' and 'disrupted' genotypes were re-fed following brief starvation, with or without exposure to rapamycin, the cognate inhibitor of the nutrient-sensing target of rapamycin (TOR). RNAseq showed that alternative mtDNA genotypes affect the temporal transcriptional response to nutrients in a rapamycin-dependent manner. Pathways most greatly affected were OXPHOS, protein metabolism and fatty acid metabolism. A distinct set of testis-specific genes was also differentially regulated in the experiment. CONCLUSIONS: Many of the differentially expressed genes between alternative mitonuclear genotypes have no direct interaction with mtDNA gene products, suggesting that the mtDNA genotype contributes to retrograde signaling from mitochondria to the nucleus. The interaction of mitochondrial genotype (mtDNA) with rapamycin treatment identifies new links between mitochondria and the nutrient-sensing mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway.

Autologous stem cell transplantation vs bortezomib based chemotheraphy for the first-line treatment of systemic light chain amyloidosis in the UK.

OBJECTIVES: The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. METHODS: Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001 and 2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity-matched scoring approach. RESULTS: A total of 136 propensity score-matched patients were included (ASCT n = 68, bortezomib n = 68). There was no significant difference in overall survival at two years (P = .908, HR: 0.95, CI: 0.41-2.20). For ASCT vs bortezomib: overall haematological response rate at 6 months was 90.6% vs 92.5%; organ response at 12 months: cardiac (70.0% vs 54%, P > .999), renal (74% vs 24%, P = .463) liver (21% vs 22%, P = .048); median progression-free survival (50 vs 42 months P = .058, HR: 0.61, CI: 0.37-1.02) and time to next treatment (68 vs 45 months, P = .145, HR: 0.61, CI: 0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs 23, Chi-squared P = .004) and 48 months (57 vs 41, Chi-squared P = .004). CONCLUSIONS: This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed.

The COVID-19 pandemic in francophone West Africa: from the first cases to responses in seven countries.

BACKGROUND: In early March 2020, the COVID-19 pandemic hit West Africa. In response, countries in the region quickly set up crisis management committees and implemented drastic measures to stem the spread of the SARS-CoV-2 virus. The objective of this article is to analyse the epidemiological evolution of COVID-19 in seven Francophone West African countries (Benin, Burkina Faso, Côte d'Ivoire, Guinea, Mali, Niger, Senegal) as well as the public health measures decided upon during the first 7 months of the pandemic. METHODS: Our method is based on quantitative and qualitative data from the pooling of information from a COVID-19 data platform and collected by a network of interdisciplinary collaborators present in the seven countries. Descriptive and spatial analyses of quantitative epidemiological data, as well as content analyses of qualitative data on public measures and management committees were performed. RESULTS: Attack rates (October 2020) for COVID-19 have ranged from 20 per 100,000 inhabitants (Benin) to more than 94 per 100,000 inhabitants (Senegal). All these countries reacted quickly to the crisis, in some cases before the first reported infection, and implemented public measures in a relatively homogeneous manner. None of the countries implemented country-wide lockdowns, but some implemented partial or local containment measures. At the end of June 2020, countries began to lift certain restrictive measures, sometimes under pressure from the general population or from certain economic sectors. CONCLUSION: Much research on COVID-19 remains to be conducted in West Africa to better understand the dynamics of the pandemic, and to further examine the state responses to ensure their appropriateness and adaptation to the national contexts.

Cerebral venous thrombosis in a sub-saharan African country: A preliminary monocentric study of a 70 case series at the neurology department of Fann teaching hospital in Dakar - Senegal.

INTRODUCTION: Cerebral venous thrombosis (CVT) are underdiagnosed in sub-saharan Africa where publications are uncommon. Our study aim was to describe the CVT diagnostic and therapeutic features through a senegalese case series. PATIENTS AND METHOD: A monocentric retrospective and prospective study was conducted at the adult Neurology department of Fann Teaching Hospital in Dakar (Senegal), between January 01, 2013 and April 30, 2020. It had included all CVT cases diagnosed by neurovascular imaging. RESULTS: Seventy CVT cases were collected including 48 women (68.6%). The average age of the patients was 35.2±14 years. The main neurological signs were headache (92.8%) and motor deficit (41.4%), with subacute onset in 67.2% of cases. The superior sagittal sinus (54.3%) and the transverse sinus (38.6%) were the most affected with multiple involvements in 27 patients (38.6%). Thirty patients (42.8%) had indirect parenchymal signs such as venous infarction (15.7%), cerebral edema (11.4%) or intracerebral hemorrhage (12.8%). The etiological factors were mostly infectious (41.4%) with meningoencephalitis (12.8%) and otorhinolaryngological infection (10%). Gyneco-obstetric factors (27%) and Behçet's disease (7%) were the main aseptic factors. In the short-term clinical course, curative anticoagulation (98.6%) had enabled a favourable outcome (mRS 0-1) in half of the patients. CONCLUSION: Our study, the largest series in sub-saharan Africa to this date, confirms that CVT is a young women disease. Infectious etiology is the most frequent at the Fann national teaching hospital (41.4% in Dakar against 6.5% in Germaine Bousser's series) even if the etiological assessment is limited by financial constraints (no coagulopathy/thrombophilia check-up).

Projecting potential impact of COVID-19 on major cereal crops in Senegal and Burkina Faso using crop simulation models.

CONTEXT: The rapid emergence of COVID-19 could have direct and indirect impacts on food production systems and livelihoods of farmers. From the farming perspective, disruption of critical input availability, supply chains and labor, influence crop management. Disruptions to food systems can affect (a) planting area; and (b) crop yields. OBJECTIVES: To quantify the impacts of COVID-19 on major cereal crop's production and their cascading impact on national economy and related policies. METHODS: We used the calibrated crop simulation model (DSSAT suite) to project the impact of potential changes in planting area and grain yield of four major cereal crops (i.e., rice, maize, sorghum, and millet) in Senegal and Burkina Faso in terms of yield, total production, crop value and contribution to agricultural gross domestic product (GDP). Appropriate data (i.e., weather, soil, crop, and management practices) for the specific agroecological zones were used as an input in the model. RESULTS AND CONCLUSIONS: The simulated yields for 2020 were then used to estimate crop production at country scale for the matrix of different scenarios of planting area and yield change (-15, -10, -5, 0, +5, +10%). Depending on the scenario, changes in total production of four cereals combined at country levels varied from 1.47 M tons to 2.47 M tons in Senegal and 4.51 M tons to 7.52 M tons in Burkina Faso. The economic value of all four cereals under different scenarios ranged from $771 Million (M) to $1292 M in Senegal and from $1251 M to $2098 M in Burkina Faso. These estimated total crop values under different scenarios were compared with total agricultural GDP of the country (in 2019 terms which was $3995 M in Senegal and $3957 M in Burkina Faso) to assess the economic impact of the pandemic on major cereal grain production. Based on the scenarios, the impact on total agricultural GDP can change -7% to +6% in Senegal and - 8% to +9% in Burkina Faso. SIGNIFICANCE: Results obtained from this modeling exercise will be valuable to policymakers and end-to-end value chain practitioners to prepare and develop appropriate policies to cope or manage the impact of COVID-19 on food systems.

Tragedy in Haiti: Suicidality, PTSD, and Depression Associated with Intimate Partner Violence Among Haitian Women After the 2010 Earthquake.

Across the world, suicidal behaviors are responsible for more than one million deaths each year. In Haiti, suicidal behaviors were found to be related to intimate partner violence (IPV) against women. This study was conducted after the 2010 earthquake in Haiti and women were asked about IPV before and after that event. A sample of women between 18 and 44 years of age responded to a questionnaire about physical, psychological, or sexual abuse by an intimate or non-intimate partner. The women were divided into two groups: (a) women who were abused by partners (n = 133) and (b) women who were not abused (n = 75). Those who were abused had 2.2 times higher odds for suicidal thoughts and 1.9 times higher odds for suicidal attempts and were significantly more likely to suffer from depression and PTSD. For each 1-unit increase in a measured PTSD score, the odds of being abused increased by 105.7%. For each 1-unit increase in the measured depression score, the odds of being abused increased by 14.9%.

Medical Mistrust Among Black Women in America.

This qualitative research study highlights medical mistrust as a significant barrier to quality health care for Black women. Unraveling mistrust is essential for reducing health disparities and improving well-being for women and their families. Three research sites were included: Florida, Ohio, and the U.S. Virgin Islands. Three 90-minute focus groups were convened with 10 women in each of them. The discussions were recorded. Five themes will be discussed through the voices of women from each of the sites. Mistrust of healthcare professionals was associated with fears about being rejected, embarrassed, and misunderstood during the clinical encounter. Others reported that providers who were reluctant to make physical contact with them during the clinical visits provoked feelings that the color of their skin might seem "dirty." Finally, this research will help to inform discussions about COVID-19 vaccine hesitancy, which remains a critical health concern among Black women and healthcare providers.

Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis.

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease. METHODS: We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V1221 variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients. RESULTS: There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9-27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally ( P<0.001) and had worse measures of cardiac disease ( P<0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival ( P<0.001) in comparison with the other subgroups. CONCLUSIONS: ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.

Cardiac biomarkers are prognostic in systemic light chain amyloidosis with no cardiac involvement by standard criteria.

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55 ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 µmol/L and mean left ventricular septal wall thickness, 10 mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (n=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (P<0.008, hazard ratio [HR] 3.180, confidence interval [CI]: 1.349-7.495) and cardiac involvement on magnetic resonance imaging (P=0.026, HR=5.360, CI: 1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.

Cytomegalovirus reactivation after bortezomib treatment for multiple myeloma and light chain amyloidosis.

OBJECTIVE: Cytomegalovirus (CMV) is an opportunistic herpesvirus, and reactivation of infection is possible in immunocompromised patients. Historically, the risk for haematology patients is restricted to those treated with an allogeneic transplant or T-cell depleting agents. Bortezomib is a highly efficacious proteasome inhibitor widely used to treat multiple myeloma and light chain (AL) amyloidosis patients. The objective of this small prospective study was to quantify the risk of CMV reactivation associated with bortezomib treatment. METHODS: Fifty-seven consecutive multiple myeloma or AL amyloidosis patients commencing bortezomib-based therapy were included. Viral copy numbers were established at baseline and then at fortnightly intervals during treatment. Pre-emptive anti-viral treatment was initiated in patients with a viral load >7500 copies/mL. RESULTS: Reactivation of CMV was detected in 39% (n = 12/31) of seropositive bortezomib treated patients compared with 0% of CMV seronegative patients. Detectable DNAemia developed during the first two cycles of treatment in 83% (n = 10/12) patients. Anti-viral treatment was initiated in 42% (n = 5/12), but no cases of active CMV disease were seen. CONCLUSION: This study suggests that there is a substantial risk of CMV reactivation in CMV-seropositive plasma cell dyscrasia patients treated with bortezomib.

A DNA Repair Inhibitor Isolated from an Ecuadorian Fungal Endophyte Exhibits Synthetic Lethality in PTEN-Deficient Glioblastoma.

Disruption of the tumor suppressor PTEN, either at the protein or genomic level, plays an important role in human cancer development. The high frequency of PTEN deficiency reported across several cancer subtypes positions therapeutic approaches that exploit PTEN loss-of-function with the ability to significantly impact the treatment strategies of a large patient population. Here, we report that an endophytic fungus isolated from a medicinal plant produces an inhibitor of DNA double-strand-break repair. Furthermore, the novel alkaloid product, which we have named irrepairzepine (1), demonstrated synthetic lethal targeting in PTEN-deficient glioblastoma cells. Our results uncover a new therapeutic lead for PTEN-deficient cancers and an important molecular tool toward enhancing the efficacy of current cancer treatments.