The HTR1A -1019C>G genotype was associated with major depression in the Utah population. Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with ...the HTR1A -1019G allele revealed a linkage peak on chromosome 10 (maximum HLOD=4.4). Sequencing of all known genes in the linkage region revealed disease-segregating single-nucleotide polymorphisms (SNPs) in LHPP. LHPP SNPs were also associated with major depression in both Utah and Ashkenazi populations. Consistent with the linkage evidence, LHPP associations depended on HTR1A genotype. Lhpp or a product of a collinear brain-specific transcript, therefore, may interact with Htr1a in the pathogenesis of major depression.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The respiratory release of carbon dioxide (CO₂) from soil is a major yet poorly understood flux in the global carbon cycle. Climatic warming is hypothesized to increase rates of soil respiration, ...potentially fueling further increases in global temperatures. However, despite considerable scientific attention in recent decades, the overall response of soil respiration to anticipated climatic warming remains unclear. We synthesize the largest global dataset to date of soil respiration, moisture, and temperature measurements, totaling >3,800 observations representing 27 temperature manipulation studies, spanning nine biomes and over 2 decades of warming. Our analysis reveals no significant differences in the temperature sensitivity of soil respiration between control and warmed plots in all biomes, with the exception of deserts and boreal forests. Thus, our data provide limited evidence of acclimation of soil respiration to experimental warming in several major biome types, contrary to the results from multiple single-site studies. Moreover, across all nondesert biomes, respiration rates with and without experimental warming follow a Gaussian response, increasing with soil temperature up to a threshold of ∼25 °C, above which respiration rates decrease with further increases in temperature. This consistent decrease in temperature sensitivity at higher temperatures demonstrates that rising global temperatures may result in regionally variable responses in soil respiration, with colder climates being considerably more responsive to increased ambient temperatures compared with warmer regions. Our analysis adds a unique cross-biome perspective on the temperature response of soil respiration, information critical to improving our mechanistic understanding of how soil carbon dynamics change with climatic warming.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Agroforestry systems have the potential to sequester carbon and offer numerous benefits to rural communities, but their capacity to offer valuable cooling services has not been quantified on ...continental scales. Here, we find that trees in pasturelands ("silvopasture") across Latin America and Africa can offer substantial cooling benefits. These cooling benefits increase linearly by -0.32 °C to -2.4 °C per 10 metric tons of woody carbon per hectare, and importantly do not depend on the spatial extent of the silvopasture systems. Thus, even smallholders can reap important cooling services from intensifying their silvopasture practices. We then map where realistic (but ambitious) silvopasture expansion could counteract a substantial fraction of the local projected warming in 2050 due to climate change. Our findings indicate where and to what extent silvopasture systems can counteract local temperature increases from global climate change and help vulnerable communities adapt to a warming world.
The receptor for advanced glycation end products (RAGE) is implicated in obesogenesis. Conversely, soluble RAGE (sRAGE) competitively inhibits RAGE. Our aim was to determine the effects of ...weight-loss via alternate day fasting (ADF) on sRAGE isoforms and evaluate potential relationships with body composition.
42 obese participants were randomized to control (CON) or ADF. For 24 weeks, the ADF group consumed 25% or 125% of their caloric requirements on alternating days while the CON group did not change their diet. Body fat was measured via DXA, visceral fat (VAT) via MRI and subcutaneous fat (SAT) was derived by subtracting VAT from total fat. sRAGE isoforms were measured via ELISAs. After 24 weeks, ADF −6.8 (−9.5, −3.5)kg (Median, IQR) lost more weight than CON −0.3 (−1.9, 1.0)kg (p < 0.05). The change in endogenous secretory RAGE (esRAGE) was different between ADF 15 (−30, 78)pg/mL and CON −21 (−72, 16)pg/mL after 24 weeks (p < 0.05). To examine the effect of changes in body composition, the cohort was stratified by median weight-, fat-, SAT-, and VAT-loss. The changes in all sRAGE isoforms were different between those above and below median weight-loss (p < 0.05) with sRAGE isoforms tending to decrease in individuals below the median. Changes in total sRAGE and esRAGE were different between individuals above compared to below median fat- and SAT-loss (p < 0.05). Those above median fat-loss increased esRAGE by 29 (−5, 66)pg/mL (p < 0.05).
Improvements in body composition are related to increased sRAGE isoforms, implicating sRAGE as a potential target for the treatment of obesity.
NCT00960505.
•The control group significantly reduced their total sRAGE and cRAGE.•The alternate day fasting group was protected from reductions in sRAGE isoforms.•Those who lost more fat significantly increased their esRAGE.•Subcutaneous fat loss was negatively correlated to the change in esRAGE.•The change in cRAGE:esRAGE was negatively related to the change in adiponectin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The purpose of this population‐based prospective cohort study was to examine the effect of hormone‐replacement therapy (HRT) on the risk of fractures. The study population consisted of 7217 ...postmenopausal women aged 47‐56 years (mean, 53.3 years) at baseline from data taken from the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) in Finland. We compared fracture incidences between HRT users and nonusers. A total of 679 (9.4%) women recorded validated fractures during the 5‐year follow‐up. Of these, 268 (39%) women had a distal forearm fracture. Two thousand six hundred seventy women (37%) had used HRT >6 months during the follow‐up—one‐half of them continuously. The relative risk, estimated as hazard ratio with Cox regression, was 0.69 (95% CI, 0.58‐0.82) for any fracture and 0.49 (0.36‐0.66) for distal forearm fracture among HRT users as compared with never‐users. After adjusting for age, body mass index (BMI), number of chronic health disorders, fracture history, and time since menopause (independent risk factors) the corresponding risks were 0.67 (0.55‐0.81) and 0.53 (0.37‐0.74), respectively. The respective adjusted risks for continuous HRT users were 0.62 (0.48‐0.79) and 0.41 (0.26‐0.67). The adjusted risk of other than distal forearm fracture was 0.74 (0.55‐0.98). The results suggest that HRT has a beneficial effect on prevention of fractures in general and on that of distal forearm fracture in particular in early postmenopausal women.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, ...high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future.
The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field.
Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues.
We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 ...expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4CreSatb1f/f mice enriched for antigen-specific Tfh cells, and TGF-β-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1−/− CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4CreSatb1f/f mice accumulated tumor antigen-specific, LIGHT+CXCL13+IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-β-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.
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•Satb1−/− CD4+ T cells show heightened antigen-specific Tfh cell differentiation•SATB1-mediated suppression of Icos expression is required for Tfr cell differentiation•CD4CreSatb1f/f mice spontaneously develop intra-tumoral tertiary lymphoid structures•Tfh cell transfer elicits intra-tumoral TLS assembly and reduces tumor growth
Tertiary lymphoid structures (TLS) are associated with improved outcomes for cancer patients. Chaurio et al. demonstrate that TGF-β-mediated regulation of the genomic organizer Satb1 governs the differentiation of T follicular helper (Tfh) cells and T follicular regulatory cells. Loss of Satb1 promotes Icos expression and thereby Tfh cell differentiation, resulting in the assembly of intra-tumoral TLS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple ...myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology ...and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP
). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP
=not reached, CIMP
=1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP
=2.34, A-CIMP
=1.00; P=0.01). Hypermethylation in A-CIMP
favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP
was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP
function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP
AML should be validated prospectively.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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