Because the outcome of allogeneic hematopoietic cell transplantation (HCT) is predominantly influenced by disease type and status, it is essential to be able to stratify patients undergoing HCT by ...disease risk. The Disease Risk Index (DRI) was developed for this purpose. In this study, we analyzed 13 131 patients reported to the Center for International Blood and Marrow Transplant Research who underwent HCT between 2008 and 2010. The DRI stratified patients into 4 groups with 2-year overall survival (OS) ranging from 64% to 24% and was the strongest prognostic factor, regardless of age, conditioning intensity, graft source, or donor type. A randomly selected training subgroup of 9849 patients was used to refine the DRI, using a multivariable regression model for OS. This refined DRI had improved prediction ability for the remaining 3282 patients compared with the original DRI or other existing schemes. This validated and refined DRI can be used as a 4- or 3-group index, depending on the size of the cohort under study, for prognostication; to facilitate the interpretation of single-center, multicenter, or registry studies; to adjust center outcome data; and to stratify patients entering clinical trials that enroll patients across disease categories.
•The DRI successfully stratified patients in a very large allogeneic transplantation registry cohort.•The DRI was refined by using this cohort to build a more inclusive and conditioning intensity–independent index.
Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer
. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell ...death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies
. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.
Burns are caused by several mechanisms including flame, scald, chemical, electrical, and ionizing and non-ionizing radiation. Approximately half a million burn cases are registered annually, of which ...40 thousand patients are hospitalized and receive definitive treatment. Burn care is very resource intensive as the treatment regimens and length of hospitalization are substantial. Burn wounds are classified based on depth as superficial (first degree), partial-thickness (second degree), or full-thickness (third degree), which determines the treatment necessary for successful healing. The goal of burn wound care is to fully restore the barrier function of the tissue as quickly as possible while minimizing infection, scarring, and contracture. The aim of this review is to highlight how tissue engineering and regenerative medicine strategies are being used to address the unique challenges of burn wound healing and define the current gaps in care for both partial- and full-thickness burn injuries. This review will present the current standard of care (SOC) and provide information on various treatment options that have been tested pre-clinically or are currently in clinical trials. Due to the complexity of burn wound healing compared to other skin injuries, burn specific treatment regimens must be developed. Recently, tissue engineering and regenerative medicine strategies have been developed to improve skin regeneration that can restore normal skin physiology and limit adverse outcomes, such as infection, delayed re-epithelialization, and scarring. Our emphasis will be centered on how current clinical and pre-clinical research of pharmacological agents, biomaterials, and cellular-based therapies can be applied throughout the continuum of burn care by targeting the stages of wound healing: hemostasis, inflammation, cell proliferation, and matrix remodeling.
The combination of doxorubicin (Adriamycin) and cyclophosphamide, referred to as AC chemotherapy, is commonly used for the clinical treatment of breast and other cancers. Both agents target DNA with ...cyclophosphamide causing alkylation damage and doxorubicin stabilizing the topoisomerase II-DNA complex. We hypothesize a new mechanism of action whereby both agents work in concert. DNA alkylating agents, such as nitrogen mustards, increase the number of apurinic/apyrimidinic (AP) sites through deglycosylation of labile alkylated bases. Herein, we demonstrate that anthracyclines with aldehyde-reactive primary and secondary amines form covalent Schiff base adducts with AP sites in a 12-mer DNA duplex, calf thymus DNA, and MDA-MB-231 human breast cancer cells treated with nor-nitrogen mustard and the anthracycline mitoxantrone. The anthracycline-AP site conjugates are characterized and quantified by mass spectrometry after NaB(CN)H
or NaBH
reduction of the Schiff base. If stable, the anthracycline-AP site conjugates represent bulky adducts that may block DNA replication and contribute to the cytotoxic mechanism of therapies involving combinations of anthracyclines and DNA alkylating agents.
Aflatoxin B
(AFB
) is a potent human liver carcinogen produced by certain molds, particularly
and
, which contaminate peanuts, corn, rice, cottonseed, and ground and tree nuts, principally in warm ...and humid climates. AFB
undergoes bioactivation in the liver to produce AFB
-
-8,9-epoxide, which forms the covalently bound cationic AFB
-
7-guanine (AFB
7-Gua) DNA adduct. This adduct is unstable and undergoes base-catalyzed opening of the guanine imidazolium ring to form two ring-opened diastereomeric 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxy-aflatoxin B
(AFB
-FapyGua) adducts. The AFB
formamidopyrimidine (Fapy) adducts induce G → T transversion mutations and are likely responsible for the carcinogenic effects of AFB
. Quantitative liquid chromatography-mass spectrometry (LC-MS) methods have shown that AFB
-
7-Gua is eliminated in rodent and human urine, whereas ring-opened AFB
-FapyGua adducts persist in rodent liver. However, fresh frozen biopsy tissues are seldom available for biomonitoring AFB
DNA adducts in humans, impeding research advances in this potent liver carcinogen. In contrast, formalin-fixed paraffin-embedded (FFPE) specimens used for histopathological analysis are often accessible for molecular studies. However, ensuring nucleic acid quality presents a challenge due to incomplete reversal of formalin-mediated DNA cross-links, which can preclude accurate quantitative measurements of DNA adducts. In this study, employing ion trap or high-resolution accurate Orbitrap mass spectrometry, we demonstrate that ring-opened AFB
-FapyGua adducts formed in AFB
-exposed newborn mice are stable to the formalin fixation and DNA de-cross-linking retrieval processes. The AFB
-FapyGua adducts can be detected at levels comparable to those in a match of fresh frozen liver. Orbitrap MS
measurements can detect AFB
-FapyGua at a quantification limit of 4.0 adducts per 10
bases when only 0.8 μg of DNA is assayed on the column. Thus, our breakthrough DNA retrieval technology can be adapted to screen for AFB
DNA adducts in FFPE human liver specimens from cohorts at risk of this potent liver carcinogen.
This study retrospectively reviews an aggressive multidisciplinary approach to the treatment of massive pulmonary embolism, centering on rapid diagnosis with contrast-enhanced computed tomography of ...the chest to define the location and degree of clot burden and transthoracic echocardiography to document right ventricular strain followed by immediate surgical intervention when appropriate.
Between October 1999 through February 2004, 47 patients (30 men and 17 women; median age, 58 years; age range, 24–86 years) underwent emergency surgical embolectomy for massive central pulmonary embolism. The indications for surgical intervention were (1) contraindications to thrombolysis (21/47 45%), (2) failed medical treatment (5/47 10%), and (3) right ventricular dysfunction (15/47 32%). Preoperatively, 12 (26%) of 47 patients were in cardiogenic shock, and 6 (11%) of 47 were in cardiac arrest.
There were 3 (6%) operative deaths, 2 with preoperative cardiac arrest; 2 of these 3 patients required a right ventricular assist device. In 38 (81%) patients a caval filter was placed intraoperatively. Median length of stay was 11 days (range, 3–75 days). Median follow-up was 27 months (range, 2–50 months); follow-up was 100% complete in surviving patients. There were 6 (12%) late deaths, 5 of which were from metastatic cancer. Actuarial survival at 1 and 3 years’ follow-up was 86% and 83%, respectively.
An aggressive approach to large pulmonary embolus, including rapid diagnosis and prompt surgical intervention, has improved results with surgical embolectomy. We now perform surgical pulmonary embolectomy not only in patients with large central clot burden and hemodynamic compromise but also in hemodynamically stable patients with right ventricular dysfunction documented by means of echocardiography.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target ...engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF.
This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand,
FFB-A20FMDV2. The primary endpoint was whole lung volume of distribution (V
), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in V
> 0%) of ≥80%.
Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected V
at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in V
> 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination.
This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug.
clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.
Measuring the carbon stable isotope ratio (13C/12C, expressed as δ13CCO2) in geogenic CO2 fluids is a crucial geochemical tool for studying Earth's degassing. Carbon stable isotope analysis is ...traditionally performed by bulk mass spectrometry. Although Raman spectroscopy distinguishes 12CO2 and 13CO2 isotopologue bands in spectra, using this technique to determine CO2 isotopic signature has been challenging. Here, we report on in-situ non-destructive analyses of the C stable isotopic composition of CO2, applying a novel high-resolution Raman configuration on 42 high-density CO2 fluid inclusions in mantle rocks from the Lake Tana region (Ethiopia) and El Hierro (Canary Islands). We collected two sets of three spectra with different acquisition times at high spectral resolution in each fluid inclusion. Among the 84 sets of spectra, 58 were characterised by integrated 13CO2/12CO2 band area ratios with reproducibility better than 4‰. Our results demonstrate the determination of δ13CCO2 by Raman spectroscopy in individual fluid inclusions with an error better than 2.5 ‰, which satisfactorily matches bulk mass spectrometry analyses in the same rock samples, supporting the accuracy of the measurements. We thus show that Raman Spectroscopy can provide a fundamental methodology for non-destructive, site-specific, and spatially resolved carbon isotope labelling at the microscale.
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