Clonal Hematopoiesis in Women With Breast Cancer.

Purpose: Clonal hematopoiesis (CH) has been associated with a variety of adverse outcomes, most notably hematologic malignancy and ischemic cardiovascular disease. A series of recent studies also suggest that CH may play a role in the outcomes of patients with solid tumors, including breast cancer. Here, we review the clinical and biological data that underlie potential connections between CH, inflammation, and breast cancer, with a focus on the prevalence and impact of clonal hematopoiesis of indeterminate potential in patients with breast cancer.

A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.

Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant. AT2 dysfunction underlies many lung diseases, including interstitial lung disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung disease modeling and dissection of the underlying mechanisms remain challenging due to complexities in deriving and maintaining human AT2 cells ex vivo.

Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes.

Importance: Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood.

Objective: To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk.

Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon.

LINE-1 (L1) retrotransposition is widespread in many cancers, especially those with a high burden of chromosomal rearrangements. However, whether and to what degree L1 activity directly impacts genome integrity is unclear. Here, we apply whole-genome sequencing to experimental models of L1 expression to comprehensively define the spectrum of genomic changes caused by L1.

The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation.

Nutrient sensors allow cells to adapt their metabolisms to match nutrient availability by regulating metabolic pathway expression. Many such sensors are cytosolic receptors that measure intracellular nutrient concentrations. One might expect that inducing the metabolic pathway that degrades a nutrient would reduce intracellular nutrient levels, destabilizing induction.

Target product profile for cell-based and gene-based therapies to achieve a cure for HIV.

This target product profile (TPP) highlights the minimal and optimal characteristics for ex-vivo and in-vivo cell and gene therapy-based products aimed at achieving an HIV cure (ie, durable antiretroviral-free viral control). The need for an effective, safe, scalable, affordable, accessible, and acceptable cure for HIV infection remains a major global priority. The possibilities for cell and gene therapy-based products for an HIV cure are rapidly expanding.

Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein.

The most advanced monoclonal antibodies (mAbs) and vaccines against malaria target the central repeat region or closely related sequences within the circumsporozoite protein (PfCSP). Here, using an antigen-agnostic strategy to investigate human antibody responses to whole sporozoites, we identified a class of mAbs that target a cryptic PfCSP epitope that is only exposed after cleavage and subsequent pyroglutamylation (pGlu) of the newly formed N terminus. This pGlu-CSP epitope is not targeted by current anti-PfCSP mAbs and is not included in the licensed malaria vaccines.

Mechanisms of tandem duplication in the cancer genome.

Tandem duplications (TD) are among the most frequent type of structural variant (SV) in the cancer genome. They are characterized by a single breakpoint junction that defines the boundaries and the size of the duplicated segment. Cancer-associated TDs often increase oncogene copy number or disrupt tumor suppressor gene function, and thus have important roles in tumor evolution.

Preliminary clinical performance of a Cas13a-based lateral flow assay for detecting in urine specimens.

Nucleic acid amplification testing (NAAT) for is unavailable in resource-limited settings. We previously developed a CRISPR-based lateral flow assay for detecting . We aimed to pair that assay with point-of-care DNA extraction, assess performance in clinical urine specimens, and optimize assay kinetics.

Modulation of antigen delivery and lymph node activation in nonhuman primates by saponin adjuvant saponin/monophosphoryl lipid A nanoparticle.

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in nonhuman primates (NHPs) comparing the most common clinical adjuvant aluminum hydroxide (alum) with saponin/monophosphoryl lipid A nanoparticles (SMNP), an immune-stimulating complex-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B-cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells.

Beyond the Bubble: A Debate on microRNA Sorting Into Extracellular Vesicles.

Over the past decade, a scientific field has been developed demonstrating microRNAs (miRNAs) to be actively sorted into extracellular vesicles via specific nucleotide motifs that interact with discrete RNA-binding proteins. These miRNAs are proposed to be transported into recipient cells in which they can regulate specific cellular pathways. This mechanism could have enormous potential in explaining how cells signal and regulate other cells nearby or at a distance.

Diagnosing recipient- vs. donor-derived posttransplant myelodysplastic neoplasm via targeted single-cell mutational profiling.

Background: Distinguishing donor- vs. recipient-derived myelodysplastic neoplasm (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is challenging and has direct therapeutical implications.

Methods: Here, we took a translational approach that we used in addition to conventional diagnostic techniques to resolve the origin of MDS in a 38-year-old patient with acquired aplastic anemia and evolving MDS after first allo-HSCT.

Dynamics of the blood plasma proteome during hyperacute HIV-1 infection.

The complex dynamics of protein expression in plasma during hyperacute HIV-1 infection and its relation to acute retroviral syndrome, viral control, and disease progression are largely unknown. Here, we quantify 1293 blood plasma proteins from 157 longitudinally linked plasma samples collected before, during, and after hyperacute HIV-1 infection of 54 participants from four sub-Saharan African countries. Six distinct longitudinal expression profiles are identified, of which four demonstrate a consistent decrease in protein levels following HIV-1 infection.

Global adherence to a healthy and sustainable diet and potential reduction in premature death.

The Planetary Health Diet (PHD), also known as the EAT-Lancet reference diet, was developed to optimize global dietary quality while keeping the environmental impacts of food production within sustainable planetary boundaries. We calculated current national and global adherence to the PHD using the Planetary Health Dietary Index (PHDI). In addition, we used data on diet and mortality from three large US cohorts (n = 206,404 men and women, 54,536 deaths) to estimate the total and cause-specific mortality among adults 20 y of age and older that could be prevented by shifting from current diets to the reference PHD.

Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis.

During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG).

Proteolethargy is a pathogenic mechanism in chronic disease.

The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species.

Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes.

Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes.

Beyond Single Clones: High-Throughput Sequencing in Antibody Discovery.

Antibody repertoire sequencing and display library screening are powerful approaches for antibody discovery and engineering that can connect DNA sequence with antibody function. Antibody display and screening studies have made a tremendous impact on immunology and biotechnology over the last decade, accelerated by technological advances in high-throughput DNA sequencing techniques. Indeed, bioinformatic analysis of antibody DNA library data has now taken a central role in modern antibody drug discovery, and is also critical for many ongoing studies of human immune development.

Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.

Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ.

Predictive Power of Polygenic Risk Scores for Intraocular Pressure or Vertical Cup-Disc Ratio.

Importance: Early detection of glaucoma is essential to timely monitoring and treatment, and primary open-angle glaucoma risk can be assessed by measuring intraocular pressure (IOP) or optic nerve head vertical cup-disc ratio (VCDR). Polygenic risk scores (PRSs) could provide a link between genetic effects estimated from genome-wide association studies (GWASs) and clinical applications to provide estimates of an individual's genetic risk by combining many identified variants into a score.

Objective: To construct IOP and VCDR PRSs with clinically relevant predictive power.

Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint.

The aminopeptidase, endoplasmic reticulum aminopeptidase 1 (ERAP1), trims peptides for loading into major histocompatibility complex class I (MHC class I), and loss of this activity has broad effects on the MHC class I peptidome. Here, we investigated the impact of targeting ERAP1 in immune checkpoint blockade (ICB), as MHC class I interactions mediate both activating and inhibitory functions in antitumor immunity. Loss of ERAP sensitized mouse tumor models to ICB, and this sensitivity depended on CD8 T cells and natural killer (NK) cells.

In vivo photoreceptor base editing ameliorates rhodopsin-E150K autosomal-recessive retinitis pigmentosa in mice.

Rhodopsin, the prototypical class-A G-protein coupled receptor, is a highly sensitive receptor for light that enables phototransduction in rod photoreceptors. Rhodopsin plays not only a sensory role but also a structural role as a major component of the rod outer segment disc, comprising over 90% of the protein content of the disc membrane. Mutations in which lead to structural or functional abnormalities, including the autosomal recessive E150K mutation, result in rod dysfunction and death.