The pathogenesis of primary mediastinal large B-cell lymphoma (PMBCL) is incompletely understood. Recently, specific genotypic and phenotypic features have been linked to tumor cell immune escape ...mechanisms in PMBCL. We studied 571 B-cell lymphomas with a focus on PMBCL. Using fluorescence in situ hybridization here, we report that the programmed death ligand (PDL) locus (9p24.1) is frequently and specifically rearranged in PMBCL (20%) as compared with diffuse large B-cell lymphoma, follicular lymphoma, and Hodgkin lymphoma. Rearrangement was significantly correlated with overexpression of PDL transcripts. Utilizing high-throughput sequencing techniques, we characterized novel translocations and chimeric fusion transcripts involving PDLs at base-pair resolution. Our data suggest that recurrent genomic rearrangement events underlie an immune privilege phenotype in a subset of B-cell lymphomas.
•Programmed death ligands 1 and 2 are rearranged at a frequency of 20% in PMBCL.
Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular ...filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known.
In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m
of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation.
Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m
; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m
per year 95% confidence interval {CI}, -4.11 to -2.55 and -3.23 ml per minute per 1.73 m
per year 95% CI, -3.98 to -2.47, respectively; mean difference, -0.10 ml per minute per 1.73 m
per year 95% CI, -1.18 to 0.97; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group.
In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).
Positron emission tomography (PET) radioligands (radioactively labelled tracer compounds) are extremely useful for in vivo characterization of central nervous system drug candidates, ...neurodegenerative diseases and numerous oncology targets
. Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands
, yet there exist few radiolabelling protocols for the synthesis of either, inhibiting the development of PET radioligands. The synthesis of such radioligands also needs to be very rapid owing to the short half-life of carbon-11. Here we report a versatile and rapid metallaphotoredox-catalysed method for late-stage installation of both tritium and carbon-11 into the desired compounds via methylation of pharmaceutical precursors bearing aryl and alkyl bromides. Methyl groups are among the most prevalent structural elements found in bioactive molecules, and so this synthetic approach simplifies the discovery of radioligands. To demonstrate the breadth of applicability of this technique, we perform rapid synthesis of 20 tritiated and 10 carbon-11-labelled complex pharmaceuticals and PET radioligands, including a one-step radiosynthesis of the clinically used compounds
CUCB-J and
CPHNO. We further outline the direct utility of this protocol for preclinical PET imaging and its translation to automated radiosynthesis for routine radiotracer production in human clinical imaging. We also demonstrate this protocol for the installation of other diverse and pharmaceutically useful isotopes, including carbon-14, carbon-13 and deuterium.
The recent detection of SARS-CoV-2 RNA in feces has led to speculation that it can be transmitted via the fecal-oral/ocular route. This review aims to critically evaluate the incidence of ...gastrointestinal (GI) symptoms, the quantity and infectivity of SARS-CoV-2 in feces and urine, and whether these pose an infection risk in sanitary settings, sewage networks, wastewater treatment plants, and the wider environment (e.g. rivers, lakes and marine waters). A review of 48 independent studies revealed that severe GI dysfunction is only evident in a small number of COVID-19 cases, with 11 ± 2% exhibiting diarrhea and 12 ± 3% exhibiting vomiting and nausea. In addition to these cases, SARS-CoV-2 RNA can be detected in feces from some asymptomatic, mildly- and pre-symptomatic individuals. Fecal shedding of the virus peaks in the symptomatic period and can persist for several weeks, but with declining abundances in the post-symptomatic phase. SARS-CoV-2 RNA is occasionally detected in urine, but reports in fecal samples are more frequent. The abundance of the virus genetic material in both urine (ca. 102–105 gc/ml) and feces (ca. 102–107 gc/ml) is much lower than in nasopharyngeal fluids (ca. 105–1011 gc/ml). There is strong evidence of multiplication of SARS-CoV-2 in the gut and infectious virus has occasionally been recovered from both urine and stool samples. The level and infectious capability of SARS-CoV-2 in vomit remain unknown. In comparison to enteric viruses transmitted via the fecal-oral route (e.g. norovirus, adenovirus), the likelihood of SARS-CoV-2 being transmitted via feces or urine appears much lower due to the lower relative amounts of virus present in feces/urine. The biggest risk of transmission will occur in clinical and care home settings where secondary handling of people and urine/fecal matter occurs. In addition, while SARS-CoV-2 RNA genetic material can be detected by in wastewater, this signal is greatly reduced by conventional treatment. Our analysis also suggests the likelihood of infection due to contact with sewage-contaminated water (e.g. swimming, surfing, angling) or food (e.g. salads, shellfish) is extremely low or negligible based on very low predicted abundances and limited environmental survival of SARS-CoV-2. These conclusions are corroborated by the fact that tens of million cases of COVID-19 have occurred globally, but exposure to feces or wastewater has never been implicated as a transmission vector.
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•SARS-CoV-2 RNA can be readily detected in feces and occasionally urine.•Severe GI dysfunction only occurs in a small number of cases (11 ± 2%).•Likelihood of SARS-CoV-2 being transmitted via feces appears very low.•Likelihood of infection from sewage-contaminated water or food is extremely low.
Increasing antibiotic resistant hospital-acquired infections and limited new antibiotic discovery are jeopardizing human health at global scales, although how hospitals themselves fuel antimicrobial ...resistance (AMR) in the wider environment is largely unknown. Antibiotic resistance (AR) in hospitals in countries such as India is potentially problematic because of high antibiotic use, overcrowding, and inadequate wastewater containment. Here we quantified fecal coliforms (FC), carbapenem-resistant Enterobacteriaceae (CRE), bla NDM‑1 , and selected extended-spectrum β-lactam (ESBL) resistant bacteria and genes in 12 hospital wastewater outfalls and five background sewer drains across New Delhi over two seasons. Hospital wastewaters had up to 9 orders of magnitude greater concentrations of CRE bacteria and bla NDM‑1 than local sewers (depending on the hospital), implying hospitals contribute high concentrations of AR relative to community sources in Delhi, especially during the winter. Significant correlations were found between FC levels (a fecal indictor), and CRE (r = 0.924; p = 0.005), bla NDM‑1 (r = 0.934, p = 0.009), and ESBL-resistant bacteria (r = 0.913, p = 0.010) levels across hospital wastewaters, respectively, implying that elevated CRE and bla NDM‑1 are of patient origin. However, of greater importance to global health, microbial culturing found 18 to 41% of wastewater CRE isolates (n = 1447) were on the WHO “critical pathogen” list in urgent need of new antibiotics, and 55% of CRE isolates from larger hospitals carried at least one bla NDM‑1 gene. Wastewater releases from New Delhi hospitals may pose a greater AR exposure risk to residents than believed, implying in-hospital antibiotic use must be better controlled and more effective waste treatment is needed for hospital wastewaters.
PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery ...program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN.
•CFI-400945 is a PLK4 small molecule inhibitor with significant anticancer activity•CFI-400945 causes dysregulated centriole duplication, mitotic errors, and cell death•CFI-400945 may represent a therapeutic option for a range of solid tumors
Mason et al. show that PLK4 is a potential therapeutic target in human cancers. Mason et al. further identify a PLK4 inhibitor, CFI-400945, and demonstrate its potential as a clinically useful cancer therapeutic.
Mass production and use of antibiotics and antimicrobials in medicine and agriculture have existed for over 60 years, and has substantially benefited public health and agricultural productivity ...throughout the world. However, there is growing evidence that resistance to antibiotics (AR) is increasing both in benign and pathogenic bacteria, posing an emerging threat to public and environmental health in the future. Although evidence has existed for years from clinical data of increasing AR, almost no quantitative environmental data exist that span increased industrial antibiotic production in the 1950s to the present; i.e., data that might delineate trends in AR potentially valuable for epidemiological studies. To address this critical knowledge gap, we speculated that AR levels might be apparent in historic soil archives as evidenced by antibiotic resistance gene (ARG) abundances over time. Accordingly, DNA was extracted from five long-term soil-series from different locations in The Netherlands that spanned 1940 to 2008, and 16S rRNA gene and 18 ARG abundances from different major antibiotic classes were quantified. Results show that ARG from all classes of antibiotics tested have significantly increased since 1940, but especially within the tetracyclines, with some individual ARG being >15 times more abundant now than in the 1970s. This is noteworthy because waste management procedures have broadly improved and stricter rules on nontherapeutic antibiotic use in agriculture are being promulgated. Although these data are local to The Netherlands, they suggest basal environmental levels of ARG still might be increasing, which has implications to similar locations around the world.
To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) ...score and MYC/BCL2 coexpression status (dual expressers).
Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays.
The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression).
Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.
The vast majority of antibiotic resistant genes (ARG) acquired by human pathogens have originated from the natural environment. Therefore, understanding factors that influence intrinsic levels of ARG ...in the environment could be epidemiologically significant. The selection for metal resistance often promotes AR in exposed organisms; however, the relationship between metal levels in nature and the intrinsic presence of ARG has not been fully assessed. Here, we quantified, using qPCR, the abundance of eleven ARG and compared their levels with geochemical conditions in randomly selected soils from a Scottish archive. Many ARG positively correlated with soil copper levels, with approximately half being highly significant (p<0.05); whereas chromium, nickel, lead, and iron also significantly correlated with specific ARG. Results show that geochemical metal conditions innately influence the potential for AR in soil. We suggest soil geochemical data might be used to estimate baseline gene presence on local, regional and global scales within epidemiological risk studies related to AR transmission from the environment.
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