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PubMed1975

Gonococcal ophthalmia neonatorum. Relationship of maternal factors and delivery room practices to effective control measures.

Gonococcal opthalmia (proved by cultures) occurred in 11 infants delivered at the Jewish Hospital and Medical Center of Brookly (JHMCB) during a three and one-half-year period. Two more infant had conjunctivitis with presumptive evidence of gonococci (Gram stain of eye discharge). Silver nitrate was instilled in the eyes of the neonates by registered nurses. Maternal histories of these infants showed lack of prenatal care in ten, history of gonorrhea in pregnancy in three, and positive serology (STS) in two; ten of the mothers were unmarried. The over-all incidence of gonorrhea at the JHMCB prenatal clinic screening program is very low (0.02 per cent). Prevention of neonatal gonorrheal ophthalmia depends on: vigorous screening of mothers at delivery as well as during prenatal visits, careful attention to instillation of silver nitrate in the neonates' eyes, development of serologic tests for gonorrhea, and improved bacteriologic methods for culturing the organism.

Conjunctivitis↗
PubMedDate not supplied

Comparison of tympanometry and otoscopy in establishing pass/fail referral criteria.

Impedance tests, pure tone screening, and pneumatic otoscopy were performed on two groups of children. For the second group, two physicians, one an otolaryngologist and the other a pediatrician, performed the otoscopic examination. Agreement between tympanometry and otoscopy was not influenced by the presence or absence of acoustic reflexes or passing or failing the pure tone screening, but did depend on the criteria used in classifying the tympanograms. Tympanograms classified as having significant negative pressure were those showing the poorest agreement between tympanometry and otoscopy. Between examiners, agreement in otoscopic findings was generally poor. Results are discussed as they apply to establishing pass/fail criteria for screening with impedance.

Auscultation↗
PubMed2025

An in vivo barcoded CRISPR-Cas9 screen identifies Ncoa4-mediated ferritinophagy as a dependence in Tet2-deficient hematopoiesis.

TET2 is among the most commonly mutated genes in both clonal hematopoiesis and myeloid malignancies; thus, the ability to identify selective dependencies in TET2-deficient cells has broad translational significance. Here, we identify regulators of Tet2 knockout (KO) hematopoietic stem and progenitor cell (HSPC) expansion using an in vivo CRISPR-Cas9 KO screen, in which nucleotide barcoding enabled large-scale clonal tracing of Tet2-deficient HSPCs in a physiologic setting. Our screen identified candidate genes, including Ncoa4, that are selectively required for Tet2 KO clonal outgrowth compared with wild type. Ncoa4 targets ferritin for lysosomal degradation (ferritinophagy), maintaining intracellular iron homeostasis by releasing labile iron in response to cellular demands. In Tet2-deficient HSPCs, increased mitochondrial adenosine triphosphate production correlates with increased cellular iron requirements and, in turn, promotes Ncoa4-dependent ferritinophagy. Restricting iron availability reduces Tet2 KO stem cell numbers, revealing a dependency in TET2-mutated myeloid neoplasms.

CRISPR-Cas Systems↗
PubMed2024

A novel molecular pathway of lipid accumulation in human hepatocytes caused by PFOA and PFOS.

Exposed to ubiquitously perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with non-alcoholic fatty liver disease (NAFLD), yet the underlying molecular mechanism remains elusive. The extrapolation of empirical studies correlating per- and polyfluoroalkyl substance (PFAS) exposure with NAFLD occurrence to real-life exposure was hindered by the limited availability of mechanistic data at environmentally relevant concentrations. Herein, a novel pathway mediating hepatocyte lipid accumulation by PFOA and PFOS at human-relevant dose (<10&#xa0;&#x3bc;M) was identified by integrating CRISPR-Cas9 genome screening, concentration-dependent transcriptional assay in HepG2 cell and epidemiological data mining. 1) At genetic level, nudt7 showed the highest enriched potency among 569 NAFLD-related genes, and the transcription of nudt7 was significantly downregulated by PFOA and PFOS exposure (<7 &#x3bc;M). 2) At molecular pathway, upon exposure to&#xa0;&#x2264;10-4&#xa0;&#x3bc;M PFOA and PFOS, the downregulation of nudt7 transcriptional expression triggered the reduction of Ace-CoA hydrolase activity. 3) At cellular level, increased lipids were measured in HepG2 cells with PFOA and PFOS (<2&#xa0;&#x3bc;M). Overall, we identified a novel mechanism mediated by transcriptional downregulation of nudt7 gene in hepatocellular lipid increase treated with PFOA and PFOS, which could potentially explain the NAFLD occurrence associated with exposure to PFASs in humans.

Humans↗
PubMed2019

A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism.

Adeno-associated virus (AAV) capsid modification enables the generation of recombinant vectors with tailored properties and tropism. Most approaches to date depend on random screening, enrichment, and serendipity. The approach explored here, called BRAVE (barcoded rational AAV vector evolution), enables efficient selection of engineered capsid structures on a large scale using only a single screening round in vivo. The approach stands in contrast to previous methods that require multiple generations of enrichment. With the BRAVE approach, each virus particle displays a peptide, derived from a protein, of known function on the AAV capsid surface, and a unique molecular barcode in the packaged genome. The sequencing of RNA-expressed barcodes from a single-generation in vivo screen allows the mapping of putative binding sequences from hundreds of proteins simultaneously. Using the BRAVE approach and hidden Markov model-based clustering, we present 25 synthetic capsid variants with refined properties, such as retrograde axonal transport in specific subtypes of neurons, as shown for both rodent and human dopaminergic neurons.

barcoding↗
PubMed1979

Evaluation of SICKLEQUIK, a differential solubility test for hemoglobin S.

Researchers evaluated a differential tube solubility test's ability to detect Hemoglobin S (Hb S) in sickle cell conditions. Six hundred twenty-nine blood samples, including 190 S hemoglobinopathies, were used to assess test performance. Alkaline cellulose acetate electrophoresis was used to confirm all results. The test correctly indicated the presence of Hb S in every case in which Hb S was found on electrophoresis. Six of the 198 specimens containing Hb S incorrectly differentiated the heterozygous from the homozygous state (two with Hb AS, three with Hb SF, and one with Hb SC). Electrophoresis later showed four of these samples to be inappropriate for solubility testing. Three of these specimens contained Hb SF and the other specimen contained Hb SC. One specimen from a patient with polycythemia gave a false positive result. Results were compared using different methods of centrifugation. This solubility test was found to be dependable as a screening method provided the manufacturer's directions are followed and all positive results are confirmed by electrophoresis.

Anemia, Sickle Cell↗
PubMed2026

Integrating molecular subtypes, genomics and functional dependencies to identify context-specific therapeutic vulnerabilities in small cell lung cancer.

Small cell lung cancer is one of the most aggressive malignancies, characterized by rapid tumor growth, early metastatic spread and extremely poor survival. Although most patients initially respond to platinum-based chemotherapy, relapse is almost inevitable and treatment options at recurrence remain limited. The recent introduction of immune checkpoint inhibitors has provided only modest clinical benefit, largely due to the fact that these tumors are immunologically cold. These limitations highlight the urgent need to better understand the molecular features of small cell lung cancer in order to identify more effective therapeutic strategies. In this review, we summarize current knowledge of the molecular landscape of small cell lung cancer, with particular emphasis on transcriptome-based classifications that have identified four major molecular subtypes defined by distinct transcriptional regulators and gene expression programs. We discuss how these classifications have improved the biological understanding of the disease and stimulated efforts to develop subtype-specific therapeutic strategies. At the same time, we highlight important limitations of this framework, including the remarkable transcriptional plasticity of tumor cells, which allows dynamic transitions between subtypes and may contribute to therapeutic resistance. To address these challenges, we examine additional molecular features that may represent more stable vulnerabilities, including recurrent genomic alterations, such as the widespread loss of tumor suppressor genes or oncogene amplifications through extrachromosomal DNA. We also discuss emerging approaches aimed at identifying novel context-specific cancer dependencies, including genome-scale functional screens in vitro and in vivo and genetic restraint analyses. Finally, we consider the growing potential of liquid biopsy strategies, which exploit the high level of circulating tumor DNA in patients with this disease to detect clinically relevant genomic alterations and monitor tumor evolution. Overall, this review highlights both the opportunities and challenges associated with molecular stratification in small cell lung cancer. The integration of transcriptional classifications with genomic and functional approaches may help identify more robust therapeutic vulnerabilities and guide the development of more effective treatments for this highly aggressive disease.

Cancer vulnerabilities↗
PubMed2026

Mapping cell-type- and age-dependent neuronal vulnerability through genome-wide in vivo CRISPRi screens in the mouse brain.

Current brain atlases are largely descriptive, cataloging correlative molecular snapshots such as gene expression signatures yet offering limited functional insight. Here, we develop a scalable, cell-type-resolved in vivo CRISPR interference (CRISPRi) platform enabling systematic gene function profiling in the mouse brain. Through genome-wide screens across four neuronal populations at three time points spanning youth to aging, we identify neuronal essential genes missed in vitro and define a consensus set of 269 neuronal core essential genes. The data reveal cell-type-specific genetic vulnerabilities, including divergent dependencies validated for exosome component 9 (Exosc9) and osteopetrosis-associated transmembrane protein 1 (Ostm1) between excitatory and inhibitory neurons. We uncover aging-specific dependencies enriched in mitochondrial and translational pathways, aligning with transcriptional changes in the aging human brain. Finally, we establish the CRISPRinvivo data portal as a community resource for in vivo screening. Altogether, this work provides a broadly applicable platform for in vivo functional genomics and a framework for building comprehensive gene-function brain atlases.

brain aging↗
PubMed2026

Early-Onset Colorectal Cancer: Clinical and Molecular Features with Emerging Insights from Comprehensive Genomic Profiling.

Early&#x2011;onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before 50 years of age, is increasing globally. Colorectal cancer is currently the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide, with GLOBOCAN 2024 estimating approximately 2.04 million new cases and 917,895 deaths in 2024. Recent studies indicate a sustained rise in EOCRC incidence across multiple regions and birth cohorts, with the greatest increases observed among younger adults. Although hereditary cancer syndromes account for 20-25% of EOCRC cases, most occur in the absence of known genetic predispositions or established risk factors. Emerging evidence implicates the gut microbiome as a potential contributor to EOCRC, with distinct microbial signatures differentiating it from late&#x2011;onset colorectal cancer (LOCRC) diagnosed after 50 years of age. This review synthesizes current evidence on clinical, molecular, and diagnostic features distinguishing EOCRC from LOCRC, including differences in anatomical distribution, histopathology, genomic and epigenetic alterations, microbiome composition, and immune landscape, and discusses their implications for personalised screening and therapeutic strategies. We performed a retrospective secondary analysis of comprehensive genomic and immune profiling data from 1737 patients with colorectal cancer tested between June 2021 and June 2023. The analysis showed that tumours arising in patients with EOCRC had lower tumour mutational burden than tumours diagnosed as LOCRC, whereas other immune-related biomarkers, including tumour immunogenicity score, did not remain significantly different after correction for multiple testing. Despite these emerging biological differences, current screening strategies remain largely dependent on an age threshold of 50 years, and EOCRC is not addressed by age&#x2011;specific treatment approaches. We therefore review the translational potential of emerging biomarkers, including microbial signatures and liquid biopsy approaches, and propose a framework for integrating molecular profiling into clinical practice. Finally, we highlight the unmet need for coordinated efforts to improve screening in younger populations, address fertility preservation considerations, and ensure adequate psychosocial support for patients with EOCRC.

Early-onset colorectal cancer↗
PubMed1979

Megavitamins and learning disorders: a controlled double-blind experiment.

The study investigated the effectiveness of large amounts of ascorbic acid, niacinamide, calcium pantothenate, and pyridoxine when added to a low carbohydrate-high protein diet with 20 learning disabled children. After a double-blind, 6-month period of treatment, the addition of vitamins to the diet failed to produce significant improvements when compared to the diet alone on a variety of intellectual, school achievement, perceptual, and behavioral, measures. Regardless of their group assignment, 18 children showed improvements on a parent-administered behavior checklist. However, without a diet-placebo control group, these gains may have been produced by parental enthusiasm or the children's maturation rather than dietary control. The children's urinary excretion of kryptopyrrole was unrelated to whether or not they showed pre-, post-test gains and, therefore, proved to be invalid as a screening test for "vitamin dependent (on pharmacologic doses) learning disorders."

Adolescent↗
PubMed1977

On RNA-polymerases of leukemia L 1210 origin and an enzymatic method to screen antitumor antibiotics.

Four DNA-dependent RNA-polymerases were separated from the cell homogenate of moust leukemia L1210 cell by DEAE-cellulose column chromatography and tentatively designated as Peaks I, II, III and IV in the elution order. Peak II was inactivated by the addition of alpha-amanitin and effects of antibiotics and enzymes on the RNA-polymerase activity using Peaks, I, II and a mixture of Peaks I and II were examined. The RNA-polymerases were used to screen for enzyme inhibitors produced by microbes. This enzymatic method was successfully proved to select antitumor antibiotics.

Amanitins↗
PubMed1978

The ratio of de novo unbalanced translocation to 47, trisomy 21 Down syndrome. A new method for human mutation surveillance and an apparent recent change in mutation rate resulting in human interchange trisomies in one jurisdiction.

The Down syndrome phenotype may be associated with, among other genotypes, an unbalanced Robertsonian translocation producing an "interchange trisomy" with 46 chromosomes, or 47, trisomy 21. Translocations, like specificlocus point mutations, result from a direct change in structural chromosome elements. In contrast 47, trisomy 21 results from meiotic non-disjunction. Mutation rates for interchange trisomies may be followed indirectly by determining the ratio of instances of Down syndrome associated with a new translocation mutation to those produced by 47, trisomy 21, which accounts for the bulk of the Down syndrome phenotype. This genotypic ratio can be analyzed in data from cytogenetic laboratories, clinics, and chromosome registries and does not depend upon intensive chromosome screening of newborn populations. A similar approach can be adopted to follow trends in Patau syndrome. The genotypic ratio, stratified by maternal age, may in addition, provide a sentinel index for changes in human specific-locus mutations and perhaps other adverse health consequences. Analysis of data from the New York State-North-eastern chromosome registry revealed a two- to three-fold increase in the genotypic ratio for both Down syndrome and Patau syndrome for individuals born in 1973, 1974 and 1975 compared to those born in earlier years.

Down Syndrome↗
PubMed2026

TRIM21 induces selective autophagy of viruses and bacteria.

TRIM21 is an exceptionally versatile ubiquitin ligase that can be directed by antibodies to target oligomeric protein scaffolds, viral capsids, and proteopathic aggregates for intracellular degradation. How the cell degrades these typically resistant substrates remains poorly understood. To address this, we used TRIM21 viral restriction to create a genome-wide phenotypic screen for antibody-dependent capsid degradation. We identify an antimicrobial selective macroautophagy pathway in mammalian cells, which we term "antibody-directed xenophagy" (ADX). We show that this mechanism restricts structurally diverse pathogens, including adenovirus and Salmonella. Using quantitative microscopy, we demonstrate that TRIM21 rapidly intercepts antibody-pathogen complexes, leading to ubiquitin ligase activation. Following this, selective autophagy adaptors are recruited, and viral cargoes are delivered to lysosomes. This process reduces Salmonella pathology and bacterial tissue invasion in mice. We propose that TRIM21 evolved through competition with pathogens to induce autophagy of diverse and complex substrates, potentially explaining its versatility for targeted protein degradation.

TRIM21 Protein↗
PubMed1976

Cost-effectiveness of two methods of screening for asymptomatic bacteriuria.

A comparison of two methods of screening schoolgirls for asymptomatic specimens of urine from 96.3, but that the home self-administered use of dipslides was successful in only 70.2%. The failure to obtain the return of satisfactory dipslides was most frequent in children under seven and over 11 years of age, and in children from the lower social classes; satisfactory dipslides were returned by 84% of children from social classes I, II, and III non-manual workers, but by only 58% of children from social class V and the unemployed. The cost per child screened was pounds 0.77 with the supervised method and pounds 0.26 with the dipslide method. An alternative supervised method which would have successfully screened 85% would have cost pound 0.55 per child screened. Using the home dipslide method, the cost per case of asymptomatic bacteriuria detected would vary from pounds 10.40 to pounds 20.00, depending on the age group screened.

Adolescent↗
PubMed1977

The effect of errors of diagnosis and frequency of examination on reported rates of disease.

Follow-up studies of certain diseases such as cervical dysplasia and carcinoma in situ may employ repeated screening to determine disease incidence in selected cohorts. Where errors of diagnosis occur, the true cohort experience will be distorted by an amount dependent upon the frequency of screening and the magnitude of the probabilities of incorrect diagnoses. These effects are investigated through a simple model of follow-up which employs three basic assumptions: that the probability of false positive and false negative diagnoses are constant; that individuals diagnosed as positive are treated and removed from the study, irrespective of whether or not they actually have the disease; and that fixed intervals occur between follow-up exams. The analysis permits one to assess the amount of bias introduced, and numerical examples are provided.

Biometry↗
PubMed1979

Accuracy of cord blood screening for sickle hemoglobinopathies. Three- to five-year follow-up.

The strategic advantages of neonatal diagnosis of sickle hemoglobinopathies depend on an accurate cord blood screening procedure. One hundred thirty-eight black children in whom a range of normal and abnormal hemoglobin genotypes was identified by agar gel and cellulose acetate hemoglobin electrophoresis at birth were retested by cellulose acetate three to five years later. The original cord blood diagnoses were verified in all 138, including all 26 with major sickle syndromes (SS, S-beta thalassemia, and SC). Cord blood hemoglobin electrophoresis using these techniques permits accurate neonatal diagnosis of major and minor sickle hemoglobinopathies.

Anemia, Sickle Cell↗
PubMed1977

Comparison of TRF, propranolol-glucagon, insulin and glucose stimulation tests in acromegaly.

In 7 acromegalic patients growth hormone responses were studied following administration of synthetic TRF, propranolol-glucagon, insulin, and glucose p.o. Except for the glucose tolerance test, a good reproducibility of the STH response was observed. In 5 out of the 7 patients, there was a distinct rise in the plasma STH level after TRF. All patients with a positive insulin tolerance test responded to TRF, as did the two late responders to glucagon; the early responder to the latter test did not respond to TRF. It has been suggested (Liuzzi et al. 1974a) that TRF might be used as a screening test for detecting hypothalamic dependency of the acromegaly. This study suggests that further study is required before accepting this hypothesis and that a response to a combination of tests (TRF, glucagon, insulin) might be a better screening method.

Acromegaly↗