The rockefeller university

Purpose: Curative therapies remain a significant unmet need for advanced human colorectal cancer (CRC). The aim of this study was to establish a 3-step 225Ac-DOTA pretargeted radioimmunotherapy (PRIT) system for human CRC, targeting two individual antigens: glycoprotein A33 (GPA33) and human epidermal growth factor receptor 2 (HER2). Methods: In vitro cellular uptake and internalization assays, as well as survival assays (colony forming) were performed in GPA33-and HER2-positive SW1222 human CRC cells. In vivo biodistribution and therapy studies were performed with two human CRC xenograft mouse models. Results: For both antigens, treatment with up to 74 kBq 225Ac-DOTA-PRIT in SW1222-tumored mice significantly enhanced overall survival in comparison to controls, including histologic cures. The uptake of 225Ac at the tumor correlated with antigen expression (antigen expression for GPA33:HER2 is 5:1). Cellular assays showed no significant differences in internalized fraction or nucleus-associated radioactivity between the two targets. GPA33 had a higher absorbed dose to the nucleus (1.3 Gy vs. 0.65 Gy for HER2), resulting in reduced clonogenic survival. A single cycle of either GPA33 or HER2 DOTA-PRIT (37 kBq; 193.31 Gy and 113.91 Gy (relative biological effectiveness [RBE] = 5), respectively) was equally effective. No chronic nephrotoxicity was seen at <= 20 Gy (RBE = 5). The efficacy of GPA33-directed 225Ac-DOTA-PRIT was also confirmed in a patient-derived xenograft model. Conclusion: In summary, 225Ac-DOTA-PRIT to GPA33 or HER2 was highly effective and safe in preclinical models of human CRC. Tumor response to treatment could not be predicted by nuclear absorbed dose alone, highlighting the importance of comprehensive micro-and macro-dosimetry.

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.

Objective To evaluate the relationship of skin fibroblast CD34 and alpha-smooth muscle actin (alpha-SMA) and immune cell infiltration with disease duration in diffuse cutaneous systemic sclerosis (dcSSc) and identify predictors of improvement. Methods Skin biopsies and clinical data were analyzed from patients with dcSSc enrolled in lenabasum (n = 79), belimumab (n = 18), or nilotinib (n = 8) trials. CD34 and alpha-SMA were scored semiquantitatively. Immune cells (CD20+, CD3+, and CD123+) were counted. Clinical and histologic features were compared between those with early (<18 months) versus later disease (>= 18 months). Clinical improvement was defined as >5-point decrease in modified Rodnan skin score (mRSS) at 52 weeks. An Akaike's information criterion-optimal multiple logistic regression model for clinical improvement among 68 mycophenolate mofetil (MMF) users was developed. Fibroblast spatial organization was visualized using imaging mass cytometry (IMC) in a representative sample. Results Despite similar baseline mRSS, early disease was associated with lower CD34, higher alpha-SMA, increased B cells, and greater mRSS improvement compared with later SSc. IMC demonstrated regions of CD34+ fibroblasts in superficial dermis and alpha-SMA+ fibroblasts in deeper, collagen-dense regions. Among MMF users, high CD34 and alpha-SMA predicted improvement in early SSc; however, high alpha-SMA predicted lower odds of improvement in later SSc. The probability of improvement was lowest in early SSc with alpha-SMA(low)/CD34(low) immunophenotype and later SSc with alpha-SMA(high). In later SSc, B cells were higher in alpha-SMA(high) versus alpha-SMA(low) skin. Conclusion Fibroblast immunophenotype varied by baseline disease duration and improved model performance for identifying those with improvement on MMF. Skin biopsies may be useful for refining prognosis and guiding patient management decisions.

The inclusive jet cross section is measured as a function of jet transverse momentum p(T) and rapidity y. The measurement is performed using proton-proton collision data at root s = 5.02 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 27.4 pb(-1). The jets are reconstructed with the anti-k(T) algorithm using a distance parameter of R = 0.4, within the rapidity interval |y| < 2, and across the kinematic range 0.06 < p(T)< 1 TeV. The jet cross section is unfolded from detector to particle level using the determined jet response and resolution. The results are compared to predictions of perturbative quantum chromodynamics, calculated at both next-to-leading order and next-to-next-to-leading order. The predictions are corrected for nonperturbative effects, and presented for a variety of parton distribution functions and choices of the renormalization/factorization scales and the strong coupling alpha(S).

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms5,6 for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11. This study highlights the importance of considering both the genotype and the 'transcriptotype' in analyses of the penetrance and expressivity of monogenic disorders.

Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival-uncovering a hereditary basis underlying breast cancer metastasis.

Background The combination of 2 broadly neutralizing antibodies (bNAbs), teropavimab and zinlirvimab, plus the capsid inhibitor lenacapavir, is a potential twice-yearly regimen for HIV-1 treatment. The level of bNAb susceptibility to maintain virologic suppression is unknown; therefore, we evaluated this combination in participants meeting stringent viral sensitivity criteria to only 1 of the 2 bNAbs.Methods This was a pilot study within a proof-of-concept phase 1b study.Results No serious treatment-emergent adverse events occurred and 8 of 10 participants remained virologically suppressed at week 26.Conclusions More inclusive bNAb susceptibility criteria may be appropriate for future studies of this combination treatment. Clinical Trials Registration. NCT04811040.Conclusions More inclusive bNAb susceptibility criteria may be appropriate for future studies of this combination treatment. Clinical Trials Registration. NCT04811040. A single dose of lenacapavir, teropavimab, and zinlirvimab maintained virological suppression for 6 months in 8 of 10 people with HIV-1 highly susceptible to either teropavimab or zinlirvimab. Future studies should investigate broader susceptibility criteria for using this long-acting regimen.

Complete datasets of genetic variants are key to biodiversity genomic studies. Long-read sequencing technologies allow the routine assembly of highly contiguous, haplotype-resolved reference genomes. However, even when complete, reference genomes from a single individual may bias downstream analyses and fail to adequately represent genetic diversity within a population or species. Pangenome graphs assembled from aligned collections of high-quality genomes can overcome representation bias by integrating sequence information from multiple genomes from the same population, species or genus into a single reference. Here, we review the available tools and data structures to build, visualize and manipulate pangenome graphs while providing practical examples and discussing their applications in biodiversity and conservation genomics across the tree of life.

Purpose CTLA4 deficiency is an inborn error of immunity (IEI) due to heterozygosity for germline loss-of-function variants of the CTLA4 gene located on chromosome 2q33.2. CTLA4 deficiency underlies pleiotropic immune and lymphoproliferation-mediated features with incomplete penetrance. It has been identified in hundreds of patients but copy number variants (CNVs) have been reported in only 12 kindreds, including nine which displayed large 2q33.1-2q33.2 deletions encompassing CTLA4. Methods We conducted a nationwide study in France to identify patients with 2q33 deletions encompassing CTLA4. We investigated the clinical and immunological phenotypes and genotypes of these patients. Results We identified 12 patients across six unrelated kindreds with clinical immunodeficiency. Neurological features were recorded in three patients, including one with syndromic neurodevelopmental disorder. Single- nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) array analysis, and targeted high-throughput sequencing revealed five different heterozygous 2q33 deletions of 26 kilobases to 7.12 megabases in size and encompassing one to 41 genes. We identified a contiguous gene syndrome (CGS) due to associated KLF7 deficiency in a kindred with a neurodevelopmental phenotype. Conclusion Deletions within the 2q33 region encompassing CTLA4 are rare and not extensively explored, and are probably underdiagnosed in cytogenetic practice. A literature review identified 14 different CGS loci including at least one gene responsible for an IEI. The deletions involved in IEIs should be systematically delimited, to facilitate screening for CGS.

The alpha V beta 3 receptor is a member of the integrin family of receptors, which includes 24 members involved in a variety of key biological processes. It is widely expressed in multiple cell types and is involved in cell adhesion and migration, angiogenesis and immune cell regulation. These processes play important roles in both normal placentation and placental progression through pregnancy. This review describes the potential roles of alpha V beta 3 integrin receptor throughout gestation in normal and abnormal conditions, and the need for additional studies to better define its precise contributions.