Take It with a Grain (or More) of Salt: Why Industry-Backed Dietary Guidelines Fail Americans and How To Fix Them

The U.S. Dietary Guidelines lack oversight and accountability. The result: Guidelines that reflect food industry interests instead of modern science. This deleterious guidance goes on to govern federally-subsidized food assistance programs and to influence dietary choices throughout the private sector and private life. Ultimately, the Guidelines significantly contribute to the endemic chronic disease they seek to address. The Guidelines Advisory Committee is notoriously rife with conflicts of interest, and thus most Guidelines scholarship has focused on reforming the Committee. But the 2015 and 2020 Guidelines show that these reforms are insufficient and agency-level change is necessary. In 2015, the Committee made several controversial recommendations related to red meat, ultraprocessed foods, sodium, and sustainability. Due to industry backlash, only the sodium recommendation survived in the final Guidelines published by the Secretaries of the U.S. Departments of Agriculture (USDA) and Health and Human Services (HHS). In 2020, the Secretaries, for the first time, predetermined a list of eighty topics that the Committee may consider. Absent from this list are the most contentious topics from previous years. There is little recourse because the Guidelines are not considered an agency action subject to the Administrative Procedure Act (APA), despite their vast impact on food assistance programs, healthcare practices, tort law, and more. This Note proposes two ways to bring the Guidelines within the APA’s coverage. The first is a litigation strategy, arguing that the D.C. District Court relied on erroneous reasoning when it held that the Guidelines are not an agency action subject to the APA. Second, this Note describes some ways that Congress could amend the Nutrition Act, the statute governing the Guidelines. Applying the APA to the Guidelines would allow for public participation and public challenge, greater transparency, and greater efficiency across agencies. Evidence-based Guidelines would improve overall health, reduce healthcare costs, and ensure that food assistance beneficiaries can access healthy foods. A robust set of Guidelines would improve public confidence in the recommendations and enable further food law reforms, such as amending the Farm Bill, that would make it easier for people to make healthy choices

Synergistic drug combinations from electronic health records and gene expression.

ObjectiveUsing electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.MethodWe applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.ResultsFrom EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.ConclusionsThis is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing

CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNAdamage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling.Peer reviewe

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk:a large Mendelian randomisation study

Background: Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. Methods: We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. Results: The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 x 10(-11)), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P= 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P= 0.48). Conclusions: Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven

Management of systemic sclerosis: British Society for Rheumatology guideline scope

This guideline will provide a practical roadmap for management of SSc that builds upon the previous treatment guideline to incorporate advances in evidence-based treatment and increased knowledge about assessment, classification and management. General approaches to management as well as treatment of specific complications will be covered, including lung, cardiac, renal and gastrointestinal tract disease, as well as RP, digital vasculopathy, skin manifestations, calcinosis and impact on quality of life. It will include guidance related to emerging approved therapies for interstitial lung disease and account for National Health Service England prescribing policies and national guidance relevant to SSc. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol. This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence accreditation

Internal deformation of the subducted Nazca slab inferred from seismic anisotropy

Within oceanic lithosphere a fossilized fabric is often preserved originating from the time of plate formation. Such fabric is thought to form at the mid-ocean ridge when olivine crystals align with the direction of plate spreading1, 2. It is unclear, however, whether this fossil fabric is preserved within slabs during subduction or overprinted by subduction-induced deformation. The alignment of olivine crystals, such as within fossil fabrics, can generate anisotropy that is sensed by passing seismic waves. Seismic anisotropy is therefore a useful tool for investigating the dynamics of subduction zones, but it has so far proved difficult to observe the anisotropic properties of the subducted slab itself. Here we analyse seismic anisotropy in the subducted Nazca slab beneath Peru and find that the fast direction of seismic wave propagation aligns with the contours of the slab. We use numerical modelling to simulate the olivine fabric created at the mid-ocean ridge, but find it is inconsistent with our observations of seismic anisotropy in the subducted Nazca slab. Instead we find that an orientation of the olivine crystal fast axes aligned parallel to the strike of the slab provides the best fit, consistent with along-strike extension induced by flattening of the slab during subduction (A. Kumar et al., manuscript in preparation). We conclude that the fossil fabric has been overprinted during subduction and that the Nazca slab must therefore be sufficiently weak to undergo internal deformation

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases

Recurrent Coding Sequence Variation Explains only A Small Fraction of the Genetic Architecture of Colorectal Cancer

Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10-7), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10-7); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10-

CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis

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