[Electrocardiographic findings in 385 patients recovered from myocardial infarct. According to the critera of WHO and the Minnesota codex].
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Spatially mapping the transcriptome and proteome in the same tissue section can significantly advance our understanding of heterogeneous cellular processes and connect cell type to function. Here, we present Deterministic Barcoding in Tissue sequencing plus (DBiTplus), an integrative multi-modality spatial omics approach that combines sequencing-based spatial transcriptomics and image-based spatial protein profiling on the same tissue section to enable both single-cell resolution cell typing and genome-scale interrogation of biological pathways. DBiTplus begins with in situ reverse transcription for cDNA synthesis, microfluidic delivery of DNA oligos for spatial barcoding, retrieval of barcoded cDNA using RNaseH, an enzyme that selectively degrades RNA in an RNA-DNA hybrid, preserving the intact tissue section for high-plex protein imaging with CODEX. We developed computational pipelines to register data from two distinct modalities. Performing both DBiT-seq and CODEX on the same tissue slide enables accurate cell typing in each spatial transcriptome spot and subsequently image-guided decomposition to generate single-cell resolved spatial transcriptome atlases. DBiTplus was applied to mouse embryos with limited protein markers but still demonstrated excellent integration for single-cell transcriptome decomposition, to normal human lymph nodes with high-plex protein profiling to yield a single-cell spatial transcriptome map, and to human lymphoma FFPE tissue to explore the mechanisms of lymphomagenesis and progression. DBiTplusCODEX is a unified workflow including integrative experimental procedure and computational innovation for spatially resolved single-cell atlasing and exploration of biological pathways cell-by-cell at genome-scale.
High-performance liquid chromatographic (HPLC) assays have been developed for phenylmercuric nitrate and mercuric ions in the presence of disodium edetate. Application of these methods to neomycin eye drops of the Pharmaceutical Codex and Australian Pharmaceutical Formulary, which contain both phenylmercuric nitrate and disodium edetate, show that edetate promotes approximately 20% decomposition of the phenylmercuric nitrate in the drops of the Pharmaceutical Codex but little in the drops of the Australian Pharmaceutical Formulary during sterilization by the recommended method. The reason for the stability of the organomercurial in the Australian product was determined as being due to the presence of sodium chloride in the formulation.
Spatially mapping the transcriptome and proteome in the same tissue section can significantly advance our understanding of heterogeneous cellular processes and connect cell type to function. Here, we present Deterministic Barcoding in Tissue sequencing plus (DBiTplus), an integrative multi-modality spatial omics approach that combines sequencing-based spatial transcriptomics and image-based spatial protein profiling on the same tissue section to enable both single-cell resolution cell typing and genome-scale interrogation of biological pathways. DBiTplus begins with in situ reverse transcription for cDNA synthesis, microfluidic delivery of DNA oligos for spatial barcoding, retrieval of barcoded cDNA using RNaseH, an enzyme that selectively degrades RNA in an RNA-DNA hybrid, preserving the intact tissue section for high-plex protein imaging with CODEX. We developed computational pipelines to register data from two distinct modalities. Performing both DBiT-seq and CODEX on the same tissue slide enables accurate cell typing in each spatial transcriptome spot and subsequently image-guided decomposition to generate single-cell resolved spatial transcriptome atlases. DBiTplus was applied to mouse embryos with limited protein markers but still demonstrated excellent integration for single-cell transcriptome decomposition, to normal human lymph nodes with high-plex protein profiling to yield a single-cell spatial transcriptome map, and to human lymphoma FFPE tissue to explore the mechanisms of lymphomagenesis and progression. DBiTplusCODEX is a unified workflow including integrative experimental procedure and computational innovation for spatially resolved single-cell atlasing and exploration of biological pathways cell-by-cell at genome-scale.
In every country drug control depends on the existence of technical norms which are generally represented by the Pharmacopoeia. In effects, since the beginning of XIII century, when the profession of pharmacist was for the first time established by law, pharmacopoeias have had not only the purpose of supplying the composition and the preparation of drugs, but also to establish and enforce the quality of the drugs. In the present times the pharmacopoeias adopted throughout the world by the different countries are intended mainly as a codex of specifications for the control of drug quality. These pharmacopoeias are national, regional and international. Nevertheless several difficulties can be found in the use of the pharmacopoeias for control of drugs, owing to the fact that not all the drugs, allowed and in therapeutical use are included in pharmacopoeias, and also because, in some cases, the final control is not sufficient to establish drug quality especially in the case of biological preparations. The existence of a Formulary or "Codex", beyond pharmacopoeia, may be of help for the control authorities but generally is not sufficient. Some suggestions are made in order to envisage a modern pharmacopoeia, considered as a dynamic collection of specifications of drug quality, always up to date, and thus in condition to fulfil its task for the need of the drug control by the health authorities in the aim of a better protection of public health.
Transgenic plants and genome editing technologies are revolutionizing agriculture through sustainable approaches to food security, pest management, and adaptation to climate change; but their widespread use is hampered by regulatory systems that are fragmented, ethics considerations, and an ongoing lack of trust from the general public. In contrast to other literature that evaluates regulation processes and public acceptance separately, our review paper introduces a new, holistic approach that includes both technical risk assessment from a scientific perspective, and Codex Alimentarius and OECD standards, and the socio-legal and judicial environment of how the national policy decisions are actually made. The paper provides a comparative, historical analysis of the key difference between product- and process-based risk governance in the USA, the EU, and India. Through the use of case studies with global significance like MON810 maize, Bt Brinjal, and the April 2024 Philippine Court of Appeals' order for cease-and-desist of Golden Rice, we discuss the increasing tension between administrative scientific approvals and precautionary judicial orders. We further explore the emerging exemptions to regulation of Site-Directed Nuclease (SDN-1 and SDN-2) genome edited crops which led to India's revolutionary 2025 commercialization of climate-resilient rice crops. Our review ends with a forward-looking approach to biotechnology regulation policy, making an appeal to shift from static historical dichotomies towards flexible risk-proportionate and internationally coordinated regulatory systems. Finally, we show that global success of agricultural biotechnology is not just about safety verification, but rather about establishment of transparent and communicable institutions that can transform scientific risk assessments into legitimate risk management decisions.
Familial adenomatous polyposis (FAP) is a rare, hereditary syndrome that raises the risk of developing colorectal cancer (CRC). This disease model is well suited for studying the early stages of malignant transformation. Our spatial CODEX experiments reveal that, in contrast to normal mucosa, FAP mucosa, pre-cancer polyps and colorectal cancers exhibit substantial alterations in the cell type composition and tissue microenvironment. These early alterations include: an increase in the population of cancer-associated fibroblasts (CAFs), and the inhibition of tumor infiltrated lymphocytes and cell-adhesion protein by CAFs, the transformation of memory T cells into regulatory T cells, nuclear translocation of beta-catenin from the cell membrane, a decrease in the M1:M2 macrophage ratio, a notable increase in angiogenesis events. Our studies define the early stem cell, stromal, and immune steps of colorectal cancer and may benefit early detection, and therapeutic intervention.
Interest in pesticide residues in foods has increased, and the issue of residues in imported foods has been raised as a potential public health problem. Three U.S. government agencies, EPA, FDA, and USDA, are responsible for regulating pesticides. EPA sets tolerances, and FDA and USDA enforce those tolerances. As part of its regulatory activities, FDA conducts a regulatory monitoring program that samples and analyzes each year approximately 20,000 food shipments, about 60% of which are imports. Samples of imported foods are collected at ports of entry, and are chosen on the basis of several factors rather than on a completely random basis. Raw agricultural products are emphasized. Most analyses are performed using MRMs, to make best use of FDA's resources. Using five MRMs, about half of the 300 pesticides with U.S. tolerances can be determined. Results from monitoring over the past several years have shown that nearly 60% of the imported foods sampled had no pesticide residues detected. Of those samples that were violative, 5% contained residues for which there was no U.S. tolerance, and less than 1% had over-tolerance residues. Examples are given of the various pesticide/commodity combinations that have been found to be violative. FDA is often criticized for the scope of its pesticide coverage, particularly with regard to imported foods. Some critics have promoted the idea of a 'circle of poison,' which is based on the premise that pesticides banned in the U.S. are exported and used on foods in foreign countries; then the food containing these residues is imported into the U.S. and consumed. However, FDA's testing of imported foods has shown that residues of EPA-banned pesticides are not occurring from currently purposeful uses. The violation rates for imports also have not been significantly different from those for domestic foods. This indicates that foreign producers, as well as domestic growers, generally use pesticides in a manner consistent with EPA requirements. FDA continues to broaden its information-gathering capabilities. As mandated by the PMIA of 1988, FDA will attempt to obtain pesticide use information from countries that are major food exporters to the United States. An improved data management system will also be in place, and a long-range analytical method development plan instituted. Several international organizations address the issue of pesticide residues in foods. Attempts at harmonization of national tolerances for pesticide residues have not been successful, i.e., a number of individual nations have not accepted Codex MRLs.(ABSTRACT TRUNCATED AT 400 WORDS)
The use of additives to food fulfils many purposes, as shown by the index issued by the Codex Committee on Food Additives: Acids, bases and salts; Preservatives, Antioxidants and antioxidant synergists; Anticaking agents; Colours; Emulfifiers; Thickening agents; Flour-treatment agents; Extraction solvents; Carrier solvents; Flavours (synthetic); Flavour enhancers; Non-nutritive sweeteners; Processing aids; Enzyme preparations. Many additives occur naturally in foods, but this does not exclude toxicity at higher levels. Some food additives are nutrients, or even essential nutritents, e.g. NaCl. Examples are known of food additives causing toxicity in man even when used according to regulations, e.g. cobalt in beer. In other instances, poisoning has been due to carry-over, e.g. by nitrate in cheese whey - when used for artificial feed for infants. Poisonings also occur as the result of the permitted substance being added at too high levels, by accident or carelessness, e.g. nitrite in fish. Finally, there are examples of hypersensitivity to food additives, e.g. to tartrazine and other food colours. The toxicological evaluation, based on animal feeding studies, may be complicated by impurities, e.g. orthotoluene-sulfonamide in saccharin; by transformation or disappearance of the additive in food processing in storage, e.g. bisulfite in raisins; by reaction products with food constituents, e.g. formation of ethylurethane from diethyl pyrocarbonate; by metabolic transformation products, e.g. formation in the gut of cyclohexylamine from cyclamate. Metabolic end products may differ in experimental animals and in man: guanylic acid and inosinic acid are metabolized to allantoin in the rat but to uric acid in man. The magnitude of the safety margin in man of the Acceptable Daily Intake (ADI) is not identical to the "safety factor" used when calculating the ADI. The symptoms of Chinese Restaurant Syndrome, although not hazardous, furthermore illustrate that the whole ADI cannot always be ingested as a single dose on an empty stomach with impunity.
Food irradiation has become a matter of topical interest also in the Federal Republic of Germany following applications for exemptions concerning irradiation tests of spices. After risks to human health by irradiation doses up to a level sufficient for product pasteurization were excluded, irradiation now offers a method suitable primarily for the disinfestation of fruit and decontamination of frozen and dried food. Codex Alimentarius standards which refer also to supervision and dosimetry have been established; they should be adopted as national law. However, in the majority of cases where individual countries including EC member-countries so far permitted food irradiation, these standards were not yet used. Approval irradiation technique for industrial use is available. Several industrial food irradiation plants, partly working also on a contractual basis, are already in operation in various countries. Consumer response still is largely unknown; since irradiated food is labelled, consumption of irradiated food will be decided upon by consumers.
Two analytical methods, using GLC/NPD and HPLC to analyse carbofuran residues in tomatoes, are described. Both methods have shown a high recovery rate, up to 90%, and their detection limits are below the maximum residue limit set by Codex Alimentarius Mundi for carbofuran in tomatoes. Therefore, both methods may be of use in routine analysis of this pesticide in those fruits.
Classic BCR::ABL1-negative myeloproliferative neoplasms (MPNs)-polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis-are clonal haematopoietic stem cell disorders with marked heterogeneity in clinical phenotype, disease trajectory, and therapeutic response. Genomic stratification by driver and cooperating mutations only partially accounts for this variability, leaving gaps in predicting thrombotic risk, fibrotic progression, leukaemic transformation, and treatment benefit. Proteomics bridges this gap by providing function-proximal readouts of protein abundance, post-translational modifications, pathway activity, and intercellular signalling that genomics and transcriptomics cannot capture, positioning it as a theranostic platform in which the same molecular readouts simultaneously inform diagnostic stratification and therapeutic decision-making. We propose a five-stage translational framework spanning from discovery-scale mass spectrometry and affinity-based plasma profiling to targeted validation, multicentre standardisation, and machine learning-integrated clinical panels. Proteomic evidence is synthesised across the following four disease axes: clonal fitness in haematopoietic stem and progenitor cells; bone marrow microenvironmental remodelling and fibrosis; chronic inflammation and thrombosis; and leukaemic transformation. We further describe how phosphoproteomics reveals resistance mechanisms to JAK inhibitors, including AXL-MAPK bypass and PP2A-autophagy-mediated tolerance, and how protein-level biomarkers (BCL2-BCL-XL, RAS-ERK, CAMK2G, and ROCK1/2) can guide individualised therapeutic selection. Affinity-based platforms (Olink PEA and SomaScan) and spatially resolved technologies (CODEX and single-cell proteomics) complement discovery proteomics. At present, however, this evidence base is constrained by small and heterogeneous cohorts, limited cross-platform reproducibility, and a scarcity of independent external validation for candidate protein panels. Realising this vision will require multicentre standardisation, analytically validated panel assays, and prospective clinical studies that translate molecular findings into decision-grade tools for patients with MPNs.
Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities with adult glioma, it comprises distinct disease entities. In this study, we longitudinally profile a molecularly diverse cohort of 16 pHGG patients through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of neoplastic and microenvironmental features during disease progression and treatment. We define a set of core pHGG neoplastic cell states and observe differential tumor-myeloid interactions between malignant cell phenotypes. We find that essential neuromodulators and the interferon response are upregulated post-therapy, implicating them as malignant cell-intrinsic targets. We observe an increase in oligodendrocytes upon progression and that they coordinate spatial motifs with proneural tumor cells. This multiomic atlas of longitudinal pHGG captures features of therapy response and provides a scalable reference for the study of pediatric brain tumors.