The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia ...(PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy ...number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10
), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10
) and 1.68 (P=2.18 × 10
), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10
) for all patients and 3.19 (P=1.23 × 10
) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10
), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.
Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we ...perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rγ(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma.
Greenhouse crop production in northern countries often relies heavily on supplemental lighting for year-round yield and product quality. Among the different spectra used in supplemental lighting, red ...is often considered the most efficient, but plants do not develop normally when grown solely under monochromatic red light ("red light syndrome"). Addition of blue light has been shown to aid normal development, and typical lighting spectra in greenhouse production include a mixture of red and blue light. However, it is unclear whether sunlight, as part of the light available to plants in the greenhouse, may be sufficient as a source of blue light. In a greenhouse high-wire tomato (
), we varied the percentage of blue supplemental light (in a red background) as 0, 6, 12, and 24%, while keeping total photosynthetically active radiation constant. Light was supplied as a mixture of overhead (99 μmol m
s
) and intracanopy (48 μmol m
s
) LEDs, together with sunlight. Averaged over the whole experiment (111 days), sunlight comprised 58% of total light incident onto the crop. Total biomass, yield and number of fruits increased with the addition of blue light to an optimum, suggesting that both low (0%) and high (24%) blue light intensities were suboptimal for growth. Stem and internode lengths, as well as leaf area, decreased with increases in blue light percentage. While photosynthetic capacity increased linearly with increases in blue light percentage, photosynthesis in the low blue light treatment (0%) was not low enough to suggest the occurrence of the red light syndrome. Decreased biomass at low (0%) blue light was likely caused by decreased photosynthetic light use efficiency. Conversely, decreased biomass at high (24%) blue light was likely caused by reductions in canopy light interception. We conclude that while it is not strictly necessary to add blue light to greenhouse supplemental red light to obtain a functional crop, adding some (6-12%) blue light is advantageous for growth and yield while adding 24% blue light is suboptimal for growth.
The cultivation of medical cannabis ( Cannabis sativa L.) is expanding in controlled environments, driven by evolving governmental regulations for healthcare supply. Increasing inflorescence weight ...and plant specialized metabolite (PSM) concentrations is critical, alongside maintaining product consistency. Medical cannabis is grown under different spectra and photosynthetic photon flux densities (PPFD), the interaction between spectrum and PPFD on inflorescence weight and PSM attracts attention by both industrialists and scientists. Plants were grown in climate-controlled rooms without solar light, where four spectra were applied: two low-white spectra (7B-20G-73R/Narrow and 6B-19G-75R/2Peaks), and two high-white (15B-42G-43R/Narrow and 17B-40G-43R/Broad) spectra. The low-white spectra differed in red wavelength peaks (100% 660 nm, versus 50:50% of 640:660 nm), the high-white spectra differed in spectrum broadness. All four spectra were applied at 600 and 1200 μmol m -2 s -1 . Irrespective of PPFD, white light with a dual red peak of 640 and 660 nm (6B-19G-75R/2Peaks) increased inflorescence weight, compared to white light with a single red peak of 660 nm (7B-20G-73R/Narrow) (tested at P = 0.1); this was associated with higher total plant dry matter production and a more open plant architecture, which likely enhanced light capture. At high PPFD, increasing white fraction and spectrum broadness (17B-40G-43R/Broad) produced similar inflorescence weights compared to white light with a dual red peak of 640 and 660 nm (6B-19G-75R/2Peaks). This was caused by an increase of both plant dry matter production and dry matter partitioning to the inflorescences. No spectrum or PPFD effects on cannabinoid concentrations were observed, although at high PPFD white light with a dual red peak of 640 and 660 nm (6B-19G-75R/2Peaks) increased terpenoid concentrations compared to the other spectra. At low PPFD, the combination of white light with 640 and 660 nm increased photosynthetic efficiency compared with white light with a single red peak of 660nm, indicating potential benefits in light use efficiency and promoting plant dry matter production. These results indicate that the interaction between spectrum and PPFD influences plant dry matter production. Dividing the light energy in the red waveband over both 640 and 660 nm equally shows potential in enhancing photosynthesis and plant dry matter production.
In nature, soil salinity and fluctuating light (FL) often occur concomitantly. However, it is unknown whether salt stress interacts with FL on leaf photosynthesis, architecture, biochemistry, ...pigmentation, mineral concentrations, as well as whole‐plant biomass. To elucidate this, tomato (Solanum lycopersicum) seedlings were grown under constant light (C, 200 μmol m−2 s−1) or FL (5–650 μmol m−2 s−1), in combination with no (0 mM NaCl) or moderate (80 mM NaCl) salinity, for 14 days, at identical photoperiods and daily light integrals. FL and salt stress had separate effects on leaf anatomy, biochemistry and photosynthetic capacity: FL reduced leaf thickness as well as nitrogen, chlorophyll and carotenoid contents per unit leaf area, but rarely affected steady‐state and dynamic photosynthetic properties along with abundance of key proteins in the electron transport chain. Salt stress, meanwhile, mainly disorganized chloroplast grana stacking, reduced stomatal density, size and aperture as well as photosynthetic capacity. Plant biomass was affected interactively by light regime and salt stress: FL reduced biomass in salt stressed plants by 17%, but it did not affect biomass of non‐stressed plants. Our results stress the importance of considering FL when inferring effects of salt‐stress on photosynthesis and productivity under fluctuating light intensities.
Salt stress and fluctuating light affect anatomy, biochemistry and photosynthetic traits of tomato leaves separately, but affect total plant biomass interactively. Fluctuating light reduced biomass in salt stressed plants by 17%, but did not affect biomass of non‐stressed plants.
We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its ...impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.
Incident irradiance on plant leaves often fluctuates, causing dynamic photosynthesis. Whereas steady-state photosynthetic responses to environmental factors have been extensively studied, knowledge ...of dynamic modulation of photosynthesis remains scarce and scattered. This review addresses this discrepancy by summarizing available data and identifying the research questions necessary to advance our understanding of interactions between environmental factors and dynamic behaviour of photosynthesis using a mechanistic framework. Firstly, dynamic photosynthesis is separated into sub-processes related to proton and electron transport, non-photochemical quenching, control of metabolite flux through the Calvin cycle (activation states of Rubisco and RuBP regeneration, and post-illumination metabolite turnover), and control of CO₂ supply to Rubisco (stomatal and mesophyll conductance changes). Secondly, the modulation of dynamic photosynthesis and its sub-processes by environmental factors is described. Increases in ambient CO₂ concentration and temperature (up to ~35°C) enhance rates of photosynthetic induction and decrease its loss, facilitating more efficient dynamic photosynthesis. Depending on the sensitivity of stomatal conductance, dynamic photosynthesis may additionally be modulated by air humidity. Major knowledge gaps exist regarding environmental modulation of loss of photosynthetic induction, dynamic changes in mesophyll conductance, and the extent of limitations imposed by stomatal conductance for different species and environmental conditions. The study of mutants or genetic transformants for specific processes under various environmental conditions could provide significant progress in understanding the control of dynamic photosynthesis.
The study identifies potential carcinogenic health risk-zone of Chattogram city for the occurrence of trihalomethanes (THMs) at its water distribution network. The EPANET-THMs simulation model along ...with an empirical model have been adopted in the study to predict THMs content of supply water of the distribution network of the city’s Karnaphuli service area. The empirical model has estimated THMs level of supply water based on influential water quality parameters, and few of these have been used as pre-set values for subsequent EPANET simulation. The simulation (R2= 0.7) shows that THMs’ concentrations throughout the network vary from 33 to 486 μg/L. Around 60% of total junctions showed THMs concentrations above 150 μg/L, while that is above 50 μg/L for most (99%) of the junctions. Residual Free chlorine, one of the precursors for the THMs formation in distribution line, has also been simulated by EPANET considering varying applied chlorine dose at the water purification unit and wall (Kw) and bulk (Kb) decay constants. The simulated free residual chlorine peaks are found to be closer to the actual values with chlorine dose of 2 mg/L, and decay constants, Kw = 1 d−1 and Kb = 1 d−1. A mean lifetime total risk of cancer due to the presence of THMs has been found to be very high. Spatial distribution of carcinogenic risk shows that the central zone of the service area is the most vulnerable zone, followed by the western and northern zone. The first ever zone wise risk identification could be used as baseline data for operational and regulatory purposes and may raise awareness among the city’s inhabitants. Furthermore, the application of EPANET in combination with an empirical model could be an effective tool for predicting THMs’ concentration in water distribution networks in developing countries like Bangladesh to minimize the expenses of measuring THMs.
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•Carcinogenic health risk-zone of Chattogram city for THMs in water is identified.•Combination of EPANET and an empirical model as an innovative THMs’ predictive tool.•Most of the total nodal points was predicted having THMs’ content more than 80 ppb.•Zones of enhanced chlorination and junction of distribution pipes are at high-risk.•Raising awareness and monitoring of THMs at water distribution line are crucial.
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