Endogenous retroviruses (ERVs) are integrated retroviral elements that make up 8% of the human genome. However, the impact of ERVs on human health and disease is not well understood. While select ...ERVs have been implicated in diseases, including autoimmune disease and cancer, the lack of tools to analyze genome-wide, locus-specific expression of proviral autonomous ERVs has hampered the progress in the field. Here we describe a method called ERVmap, consisting of an annotated database of 3,220 human proviral ERVs and a pipeline that allows for locus-specific genome-wide identification of proviral ERVs that are transcribed based on RNA-sequencing data, and provide examples of the utility of this tool. Using ERVmap, we revealed cell-type–specific ERV expression patterns in commonly used cell lines as well as in primary cells. We identified 124 unique ERV loci that are significantly elevated in the peripheral blood mononuclear cells of patients with systemic lupus erythematosus that represent an IFN-independent signature. Finally, we identified additional tumor-associated ERVs that correlate with cytolytic activity represented by granzyme and perforin expression in breast cancer tissue samples. The open-source code of ERVmap and the accompanied web tool are made publicly available to quantify proviral ERVs in RNA-sequencing data with ease. Use of ERVmap across a range of diseases and experimental conditions has the potential to uncover novel diseaseassociated antigens and effectors involved in human health that is currently missed by focusing on protein-coding sequences.
Human endogenous retrovirus subfamily H (HERVH) is a class of transposable elements expressed preferentially in human embryonic stem cells (hESCs). Here, we report that the long terminal repeats of ...HERVH function as enhancers and that HERVH is a nuclear long noncoding RNA required to maintain hESC identity. Furthermore, HERVH is associated with OCT4, coactivators and Mediator subunits. Together, these results uncover a new role of species-specific transposable elements in hESCs.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be ...critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus MSRV-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.
Abstract Postoperative residual neuromuscular block has been recognized as a potential problem for decades, and it remains so today. Traditional pharmacologic antagonists (anticholinesterases) are ...ineffective in reversing profound and deep levels of neuromuscular block; at the opposite end of the recovery curve close to full recovery, anticholinesterases may induce paradoxical muscle weakness. The new selective relaxant-binding agent sugammadex can reverse any depth of block from aminosteroid (but not benzylisoquinolinium) relaxants; however, the effective dose to be administered should be chosen based on objective monitoring of the depth of neuromuscular block. To guide appropriate perioperative management, neuromuscular function assessment with a peripheral nerve stimulator is mandatory. Although in many settings, subjective (visual and tactile) evaluation of muscle responses is used, such evaluation has had limited success in preventing the occurrence of residual paralysis. Clinical evaluations of return of muscle strength (head lift and grip strength) or respiratory parameters (tidal volume and vital capacity) are equally insensitive at detecting neuromuscular weakness. Objective measurement (a train-of-four ratio greater than 0.90) is the only method to determine appropriate timing of tracheal extubation and ensure normal muscle function and patient safety.
BACKGROUND:Capsaicin, the active component of chili peppers, can produce sensory-selective peripheral nerve blockade. Coadministration of capsaicin and tetrodotoxin, a site-1 sodium channel blocker, ...can achieve a synergistic effect on duration of nerve blocks. However, capsaicin can be neurotoxic, and tetrodotoxin can cause systemic toxicity. We evaluated whether codelivery of capsaicin and tetrodotoxin liposomes can achieve prolonged local anesthesia without local or systemic toxicity.
METHODS:Capsaicin- and tetrodotoxin-loaded liposomes were developed. Male Sprague-Dawley rats were injected at the sciatic nerve with free capsaicin, capsaicin liposomes, free tetrodotoxin, tetrodotoxin liposomes, and blank liposomes, singly or in combination. Sensory and motor nerve blocks were assessed by a modified hotplate test and a weight-bearing test, respectively. Local toxicity was assessed by histologic scoring of tissues at the injection sites and transmission electron microscopic examination of the sciatic nerves. Systemic toxicity was assessed by rates of contralateral nerve deficits and/or mortality.
RESULTS:The combination of capsaicin liposomes and tetrodotoxin liposomes achieved a mean duration of sensory block of 18.2 hours (3.8 hours) mean (SD), far longer than that from capsaicin liposomes 0.4 hours (0.5 hours) (P < .001) or tetrodotoxin liposomes 0.4 hours (0.7 hours) (P < .001) given separately with or without the second drug in free solution. This combination caused minimal myotoxicity and muscle inflammation, and there were no changes in the percentage or diameter of unmyelinated axons. There was no systemic toxicity.
CONCLUSIONS:The combination of encapsulated tetrodotoxin and capsaicin achieved marked prolongation of nerve block. This combination did not cause detectable local or systemic toxicity. Capsaicin may be useful for its synergistic effects on other formulations even when used in very small, safe quantities.
BACKGROUND:
Despite remarkable therapeutic advances in the last 2 decades and a major improvement in survival, a number of multiple myeloma (MM) patients (pts) present a short-term outcome.
AIMS:
Our ...aim was to identify the main factors (baseline characteristics, response to therapy, relapse features) determining early mortality (EM) among a cohort of newly diagnosed symptomatic MM pts treated with novel agents.
METHODS:
We conducted a national multicenter retrospective study, including a cohort of symptomatic MM pts diagnosed between January/2010 and June/2017, treated with novel agents (bortezomib, thalidomide or lenalidomide) with the maximum age of 75 years-old and living <3 years (y) after diagnosis. We considered EM as pts living <12 months (m). All pts were dead at the time of the analysis. Data were collected from medical registries and databases. Response to treatment was evaluated according to the International Myeloma Working Group (IMWG) consensus criteria (2016). Statistical analysis was performed using STATA v.14.2 and significant levels were set at p<0.05. All risk factors with p<0.15 in the univariate model were further entered into the multivariate analysis.
RESULTS:
A total of 142 pts were included in the study, 58% male and the median age at diagnosis was 65 y (27-75). IgG was the most frequent subtype (41%), followed by IgA (32%) and light-chain κ (14%) and λ (9%). At diagnosis, renal impairment (RI) was present in 32%, extramedullary disease (EMD) in 18% and bone disease in 69% of the pts; 58.3% were in stage III and 30.6% in stage II (ISS). Fluorescent in situ hybridization analysis was performed in 76 pts, 45% presenting high-risk cytogenetic abnormalities (HRC) del(17p) and/or t(4;14) and/or t(14;16). Hypertension was present at diagnosis in 32% and diabetes in 18% pts. First-line therapy (1stL) included novel agents in 97% of the pts (64% bortezomib-based (Bor), 23% thalidomide-based (Thal) and 10% bortezomib plus IMID-based (BorIM). Response evaluation showed an overall response rate (ORR) of 73% (12% CR; 25% VGPR; 36% PR); 27% were refractory. Median time to response was 3.2m. Median number of therapy lines was 2 (1-3); 65% of the pts were refractory or progressed after 1stL therapy, 18% developed extramedullary disease (EMD) and 5 pts progressed to plasma cell leukemia. In pts receiving a 2ndL therapy, treatment-free interval was 9.2m and the most used regimens were lenalidomide (33%), Thal (25%), Bor (14%) and BorIM (11%) -based. ORR to 2ndL was 19.5% (3.4% VGPR and 16.1% PR). Six-month, 1-year and 2-years mortality was 7%, 27% and 65%, respectively. Median time until death was 18.2m; 55% of the pts died directly from disease progression (DP) and 45% from other causes infection in 68% (only 17% of whom in DP), and cardiovascular complications in 13%. In our study, prior hypertension (HR 1.53; 95% CI 1.01-2.32; p=0.046) and relapse with EMD (HR 2.0; 95% CI 1.23-3.26; p=0.005) were associated with increased risk of death. Pts≥70y also showed an increased risk of death, although not statistically significant (HR 1.42; 95% CI 0.96-2.12; p=0.081). In our cohort, refractoriness to 1stL treatment was not related to a significant increased risk of death (HR 1.48; 95% CI 0.91-2.40; p=0.11). Moreover, age, HRC, ISS stage, RI, bone disease and lactate dehydrogenase levels didn´t show a mortality predictive value. When comparing pts living <1y (EM) with pts living 1-3y, we identified the lack of at least PR (42.1% vs 21.2%, respectively; p=0.013) and a shorter time to 2ndL treatment (1.2 vs 10.0m; p=0.033) as predictors of death within the first 12m. Finally, in a multivariate analysis only the age at diagnosis >70y (HR 2.11; 95% CI 1.22-3.65; p=0.008) and EMD at relapse/progression (HR 2.55; 95% CI 1.45-4.50; p=0.001) predicted higher risk of mortality.
CONCLUSIONS:
ORR to 1stL therapy was similar to the generally expected response rate, showing that IMWG response criteria are not adequate to predict short-term outcome in the era of novel agents. The same was observed with classical baseline risk stratification features, raising the importance of defining a more accurate strategy to predict survival in MM pts. Refractory disease after 2ndL (higher than generally reported) and infections were the leading contributors to early death in our pts cohort. These data may provide new opportunities to define patient-adapted treatment strategies in order to decrease EM and improve overall survival in MM.
No relevant conflicts of interest to declare.
Background: Vaso-occlusive crisis (VOC) is the hallmark complication of sickle cell disease (SCD). The majority of SCD-related healthcare costs in the United States, estimated at $2.4 billion ...annually, are attributed to frequent healthcare utilization due to recurrent VOC (1-3). Risk factors such as the prescription of nonsteroidal anti-inflammatory drugs (NSAIDs) only without opioids, older age, and steroid treatment have been identified to be associated with readmissions in pediatric SCD patients (4, 5), but limited data exist about potential predictors for readmission in adults (6). The impact of inpatient opioid utilization on readmission was evaluated in this study.
Methods: Seventy SCD adults treated at the University of Illinois Hospital from 2012-2016 had at least one hospitalization for uncomplicated VOC that was followed by a 30-day readmission (30-DR) and at least one hospitalization without a 30-DR. One hospitalization with a 30-DR and one hospitalization without a 30-DR from each patient were used to form the discovery cohort (a total of 140 hospitalizations from 70 unique patients). Patient characteristics, inpatient laboratory values, outpatient daily opioid use before admission, and inpatient daily opioid use were collected from the electronic medical records, and the ratio of the last inpatient day opioid dose/home opioid dose before admission was calculated. Among the 70 patients in the discovery cohort, 22 patients had more than one hospitalization with a 30-DR. The additional hospitalizations with a 30-DR and matched hospitalizations from the same patient without a 30-DR were used to form a validation cohort (a total of 62 hospitalizations from 22 unique patients). A Wilcoxon signed-rank test was performed to compare the ones with a 30-DR to the ones without. The study was approved by the Institutional Review Board prior to the initiation of chart review.
Results: Among the 70 SCD patients identified, the median (IQR) age was 32.5 (25-44) years by the time of the first admission included in this cohort, and 67% were females, 76% were HbSS or Sbeta0 genotype, and 46% were on hydroxyurea before admission. The median (IQR) dose of daily outpatient opioids before the first admission was 170 (64-280) mg oral morphine equivalents (OME). When the hospitalizations without a 30-DR were compared to the ones with in the discovery cohort (Table 1), the ratio of last inpatient day opioid dose/home opioid dose was lower (1.5 vs. 1.9, p=0.024), whereas other relevant clinical variables including length of stay, pain score upon discharge, and hemoglobin or WBC upon discharge were not significantly different between the two groups (Table 1). The proportion of patients who used patient controlled analgesia (PCA) during admission, or underwent opioid dose tapering during hospitalizations, or converted IV opioids to oral ones before discharge was also comparable. In the validation cohort (Table 1), the ratio of last inpatient day opioid dose/home opioid dose in the group without a 30-DR was also lower than the ones with a 30-DR (1.4 vs. 2.0, p=0.033), whereas other clinical variables were comparable.
Summary: Here we showed that a high ratio of last inpatient day opioid dose/home opioid dose is associated with readmission risk for sickle cell patients treated for uncomplicated VOC. The results suggest that proper tapering of inpatient opioid dose in reference to patient's home opioid dose before discharge may reduce the readmission risk.
Reference:K. L. Hassell, Am J Prev Med38, S512 (Apr, 2010).S. Lanzkron, C. P. Carroll, C. Haywood, Jr., Am J Hematol85, 797 (Oct, 2010).T. L. Kauf, T. D. Coates, L. Huazhi, N. Mody-Patel, A. G. Hartzema, Am J Hematol84, 323 (Jun, 2009).L. M. Okorji, D. S. Muntz, R. I. Liem, Pediatr Blood Cancer64, (May, 2017).A. Sobota, D. A. Graham, E. J. Neufeld, M. M. Heeney, Pediatr Blood Cancer58, 61 (Jan, 2012).M. A. Brodsky et al., Am J Med130, 601 e9 (May, 2017).
No relevant conflicts of interest to declare.
Aims: The aim is to present the results of 20 years of autologous stem cell transplant (ASCT) program in multiple myeloma (MM) at our site.
Patients and methods: Since 1997 till 2017, a cohort of 348 ...patients underwent ASCT at the Department of Hemato-Oncology of the University Hospital Olomouc. Altogether 274 were 1st ASCT, 62 were 2nd transplants, the rest were tandem or third ASCT. The patients had standard baseline characteristics, including age, gender, immunoglobulin and light chain type, Durie-Salmon (DS) and International Staging System (ISS).
The induction regimens for 1st ASCT included VAD (vincristin, adriamycine, dexamethasone) in 34%, THAL in 15%, BTZ based regimens in 34%, the rest (17%) were combined polychemotherapeutic regimens. The re-induction regimens before 2nd ASCT included CAD (cyclophosphamide, adriamycine, dexamethasone) in 27%, BTZ in 31% and THAL based regimens in 18%, other patients (24%) had LEN based regimens, polychemotherapy or no re-induction. 163 patients (47%) had maintenance, mostly interferon based (25%), conventional chemotherapy based (9%) or THAL based (7%), and 53% of patients had no maintenance.
We assessed response rates, ie the rate of complete remission (CR), very good partial remission (VGPR), partial remission (PR), minimal response (MR), stable disease (SD), progressive disease (PG) and overall response rate (ORR) based on International Myeloma Working Group (IMWG) criteria. The survival measures of individual treatment lines were assessed by means of progression free survival (PFS). We assessed the efficacy of ASCT with respect to treatment line, pre-transplant and post transplant response achieved (day+100), and with respect to DS and ISS as well as to treatment modality used for induction and maintenance.
For statistical estimation we used Kaplan-Meier curves, Log rank test (Mantel-Cox), Post-hoc tests according to Dunn, Pearson ChiSquare test, Fisher´s Exact Test, Kruskal-Wallis test, and McNemar-Bowker Test.
Results: The response rates after 1st ASCT were following: CR 32,1%, VGPR 26,5%. PR 34,8%, MR and SD 3% and PG 3,4%. Median PFS after 1st ASCT was 35 months and it corresponded to the depth of treatment response: CR 48 months, VGPR 36 months, PR 33 months, MR and SD 13 months, PG 9 months, p<0,0001. Pre-transplant responses showed a trend towards better outcomes with deeper responses but beyond statistical significance (p = 0,077). Advanced DS stage correlated with worse PFS (stage I 58 months, stage II 42 months, stage III 31 months). Patients under age 59 years tended to have slightly better PFS (37 vs 34 months, p = 0,078).
Both pre and posttransplant responses were significantly better after novel drugs than conventional chemotherapy, still, there was no statistically significant difference in PFS. None of the maintenance (chemotherapy, interferon, THAL-based) lead to a better PFS. There were very few patients treated with BTZ, LEN or ixazomib maintenance precluding valid statistical analysis. There were no differences in either responses or PFS with regard to treatment line but there were only 19 patients not having ASCT as their first regimen.
The response rates after 2nd ASCT were as follows: CR 26,7%, VGPR 13,3%, PR 38,3%, MR+SD 8,3% and PG 13,3%. Median PFS after 2nd ASCT was 20 months, decreasing with inferior responses (CR 34,8 months, VGPR 22,5 months, PR 33,1 months, MR and SD 18,8 months, PG 6,6 months p<0,0001). There were no differences in PFS with respect to either ISS, DS stage or re-induction regimen. Patients transplanted in their first relapse tended to have better PFS than in later relapses.
Conclusion: The use of ASCT is still the gold standard in MM. Regardless of treatment line, it achieves significant outcomes. Novel drugs induce deeper pre-transplant responses, still, the major advantage against conventional chemotherapy is in the speed of response and absence of severe adverse events, enabling more patients to reach ASCT. Maintenance therapy accounts for better survival, however, this is true only for novel drugs (such as bortezomib, lenalidomide) whereas older modalities including interferone, post-transplant chemotherapy, steroids or thalidomide do not possess such activity. The second ASCT is comparable to to current treatment modalities in relapsed MM with fair post-transplant outcomes as well as PFS, with high rate of complete responses.
Supported by the grant IGA-LF-2018-004 andMH CR - RVO (FNOl, 00098892).
No relevant conflicts of interest to declare.
Objective: In the last decade the outcome in multiple myeloma in CHINA has greatly improved due to the new, effective therapies including PIs and Imids. But responses to treatment and survival ...remains heterogeneous because of patient characteristic, disease biology and mechanisms of drug resistance. More and more studies have established the link between depth of response and improved PFS and OS. multiparameter-flow cytometry (MFC) is a main method to detect minimal residual disease(MRD) in myeloma. Sensitivity will be at least at 10-4 to 10-5 by 10-color MFC. Imaging techniques such as PET-CT are important for EMD and bone MRD detection. whole body DWI-MRI is a new imaging technique by mean of the apparent diffusion coefficient(ADC) which can qualify the depth of response to antineoplastic treatment. This study was designed to evaluate the prognostic significance of MRD by 10-color MFC and imaging to the MM patients after induction.Methods: 102 patients with newly diagnosed MM were enrolled at the First Affiliated Hospital of Soochow University from July 2015 to July 2017. All patients were diagnosed and the response were assessed by IMWG criteria. The median of age was 58 (31-75).There were 46 patients with IgG type , 24 IgA , 14 light chain, 18 others. 34 Patients in ISS stageⅠ,34 in stage Ⅱ, 30 in stage Ⅲ. All patients received 4-6 cycles of triplet bortezomib based or lenalidomide based induction therapy. Transplantation available patients received APBSCT with BUCY condition followed by 4-6 cycles of bortezomib based or lenalidomide based consolidation which were given to transplantation unavailable patients too. Lenalidomide and thalidomide were used for over 2y of maintenance therapy. Bone marrow aspirates for MRD imaging MRD assessment were obtained at the end of induction and 1year after ASCT.The median of follow-up was 13 (2-29) months.Results: According to MRD by MFC and imaging after induction therapy and 1 year after ASCT, the patients were divided into different groups. MFC negativity was 33%(29/88) after induction therapy compared with 63%(32/51) after ASCT (X2=11.636,P=0.001). After induction therapy, the median PFS was 22 months for MRD positive group compared with not reached with MRD negative group by MFC (P=0.042) in patients with very good partial remission(VGPR) and above. The 2 years PFS was 100% for those with MRD negative compared with 60% for MRD positive by imaging. The 2 years PFS was 80% for those have multiclonal normal plasma cells compared with 52.6% for those without. The median PFS was not reached for MFC MRD negative patients 1 year after ASCT compared with 20 months for positive patients. (P=0.002). Multivariate analysis including high risk cytogenetics(17p-, t(4;14), t(14;16)), sex, age, ISS, chemotherapy, ASCT, CR/VGPR, normal PCs showed that the MFC MRD and ASCT were independent prognostic factor.Conclusions: Patients with MFC MRD negative after induction therapy or ASCT is a better prognostic marker than CR or even the best marker. Imaging MRD negativity and the appearance of normal plasma cells in the bone marrow suggests a better prognosis.We will have a try to do more research on overall survival(OS),include longer follow-up and a larger number of patients enrolled.
No relevant conflicts of interest to declare.
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