Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein.

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

Isolation of human antibodies against influenza B neuraminidase and mechanisms of protection at the airway interface.

Influenza B viruses (IBVs) comprise a substantial portion of the circulating seasonal human influenza viruses. Here, we describe the isolation of human monoclonal antibodies (mAbs) that recognized the IBV neuraminidase (NA) glycoprotein from an individual following seasonal vaccination. Competition-binding experiments suggested the antibodies recognized two major antigenic sites. One group, which included mAb FluB-393, broadly inhibited IBV NA sialidase activity, protected prophylactically in vivo, and bound to the lateral corner of NA. The second group contained an active site mAb, FluB-400, that broadly inhibited IBV NA sialidase activity and virus replication in vitro in primary human respiratory epithelial cell cultures and protected against IBV in vivo when administered systemically or intranasally. Overall, the findings described here shape our mechanistic understanding of the human immune response to the IBV NA glycoprotein through the demonstration of two mAb delivery routes for protection against IBV and the identification of potential IBV therapeutic candidates.

Computationally restoring the potency of a clinical antibody against Omicron.

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1-3 and revealed how quickly viral escape can curtail effective options4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4-6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.

Potently neutralizing and protective human antibodies against SARS-CoV-2.

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health1 and the medical countermeasures available so far are limited2,3. Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-24. Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein5, and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (SRBD) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the SRBD, as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents.

Vision Correction Habits After COVID-19 Onset in Spectacle and Contact Lens Wearers.

PURPOSE: To determine how vision correction habits changed after the 2019 coronavirus disease (COVID-19) pandemic onset. METHODS: Participants reported vision correction habits, refractive error, screen time, mask wearing time, and dry eye symptoms since the COVID-19 pandemic onset through email survey. RESULTS: A total of 133 participants completed the survey. Worsening dry eye symptoms were associated with increased screen time ( P =0.04). Hours per day of spectacle wear increased by approximately 1 hr ( P =0.001) and was associated with increased screen time ( P =0.002). Worsening dry eye symptoms were associated with increased days per week of spectacle wear ( P =0.02). Participants wore contact lenses about one day per week less than before the pandemic ( P =0.0001). Increased mask wearing time was associated with increased days per week of contact lens wear ( P =0.03). CONCLUSIONS: After pandemic onset, hours per day of spectacle wear increased, and days per week of contact lens wear decreased. Increases in hourly spectacle wear were associated with increased screen time, whereas increased daily contact lens wear was associated with increased mask wear time, suggesting that spectacles may be preferred for screen time activities and contact lenses for mask wear.

Maturing heart muscle cells: Mechanisms and transcriptomic insights.

Cardiomyocyte (CM) maturation is the transformation of differentiated fetal CMs into adult CMs that involves changes in morphology, cell function and metabolism, and the transcriptome. This process is, however, incomplete and ultimately arrested in pluripotent stem cell-derived CMs (PSC-CMs) in culture, which hinders their broad biomedical application. For this reason, enormous efforts are currently being made with the goal of generating mature PSC-CMs. In this review, we summarize key aspects of maturation observed in native CMs and discuss recent findings on the factors and mechanisms that regulate the process. Particular emphasis is put on transcriptional regulation and single-cell RNA-sequencing analysis that has emerged as a key tool to study time-series gene regulation and to determine the maturation state. We then discuss different biomimetic strategies to enhance PSC-CM maturation and discuss their effects at the single cell transcriptomic and functional levels.

The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change.

PURPOSE: Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact. METHODS: Rates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 to 2021. RESULTS: We found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared with MGPs (32.6%; P < .0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; P < .0001), whereas the use of GS compared with ES had no impact (22.2% vs 22.6%; P = ns). CONCLUSION: The high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources toward important VUS follow-up.

Impact of Mask-Associated Dry Eye on Symptom Score.

OBJECTIVES: Owing to widespread mask use during the COVID-19 pandemic and clinical reports tying mask use with dryness, this study endeavors to determine if mask use is linked to symptoms of dry eye. METHODS: A prospective, cross-sectional survey study was performed. The survey used a modified Standard Patient Evaluation of Eye Dryness Questionnaire (SPEED, TearScience, Morrisville, NC) within 15 min of the beginning and discontinuation of mask wear. The survey also asked about mask wear time, mask style, visual correction, age, and gender. RESULTS: The change in SPEED scores was statistically significant ( P =0.03) between participants with mild SPEED score at baseline (0-9) versus severe SPEED score at baseline (10-28) (n=77: 59 female, 16 male, 1 nonbinary, and 1 declined to answer; range 22-55 years old). Participants in the severe group used masks with nose wire more than the mild group ( P =0.03). CONCLUSIONS: In this sample, dry eye symptoms were most exacerbated with mask wear in those that had mild initial symptom scores compared with those with severe symptom scores at baseline. The use of nose wire masks may be protective, as the severe group used this type more and had significantly less exacerbation of symptoms postmask wear.

Racial Disparities in ICU Outcomes: A Systematic Review.

OBJECTIVES: Racial disparities in the United States healthcare system are well described across a variety of clinical settings. The ICU is a clinical environment with a higher acuity and mortality rate, potentially compounding the impact of disparities on patients. We sought to systematically analyze the literature to assess the prevalence of racial disparities in the ICU. DATA SOURCES: We conducted a comprehensive search of PubMed/MEDLINE, Scopus, CINAHL, and the Cochrane Library. STUDY SELECTION: We identified articles that evaluated racial differences on outcomes among ICU patients in the United States. Two authors independently screened and selected articles for inclusion. DATA EXTRACTION: We dual-extracted study characteristics and outcomes that assessed for disparities in care (e.g., in-hospital mortality, ICU length of stay). Studies were assessed for bias using the Newcastle-Ottawa Scale. DATA SYNTHESIS: Of 1,325 articles screened, 25 articles were included (n = 751,796 patients). Studies demonstrated race-based differences in outcomes, including higher mortality rates for Black patients when compared with White patients. However, when controlling for confounding variables, such as severity of illness and hospital type, mortality differences based on race were no longer observed. Additionally, results revealed that Black patients experienced greater financial impacts during an ICU admission, were less likely to receive early tracheostomy, and were less likely to receive timely antibiotics than White patients. Many studies also observed differences in patients' end-of-life care, including lower rates on the quality of dying, less advanced care planning, and higher intensity of interventions at the end of life for Black patients. CONCLUSIONS: This systematic review found significant differences in the care and outcomes among ICU patients of different races. Mortality differences were largely explained by accompanying demographic and patient factors, highlighting the effect of structural inequalities on racial differences in mortality in the ICU. This systematic review provides evidence that structural inequalities in care persist in the ICU, which contribute to racial disparities in care. Future research should evaluate interventions to address inequality in the ICU.

Emotional impact of compassionate extubation on respiratory therapists and nurses: A pilot study.

Background: Compassionate extubation (CE) refers to withdrawing mechanical ventilation and allowing a patient to die peacefully at the end of life. The primary objective of this pilot study was to quantify the emotional impact of CE on Respiratory Therapists (RT) and Registered Nurses (RNs). Methods: This pilot survey was conducted between March and April 2021 at an academic medical center among RTs and RNs. It included questions on participants' demographics, work characteristics, and Impact of Events (IES) scale to assess the subjective stress caused by CE. Data were analyzed using descriptive and χ2 statistics. Results: Among 20 participants, 18 (90%) were females, 12 (60%) were in the 20-40-year age group, 12 (60%) were RTs, and 8 (40%) RNs. Around 15 (75%) participants worked day shifts with a weekly average of 3-4 shifts, and 14 (70%) performed/observed CE within 1 month before taking this survey. CE performed/observed in a month was ≤2 among 15 (75%) and 3-5 among 4 (20%) participants. Mean total IES score was 16.7 (12.3) among all participants representing 7 (35%) having low, 6 (30%) moderate, and 7 (35%) high emotional impact when performing CE. Risk of developing post-traumatic stress disorder (PTSD) was present in 6 (30%) participants. A significantly higher number of participants in the low impact group were satisfied with the institutional CE process (p = 0.043) than those in the medium/high impact group. Conclusion: This pilot study findings reveal that RTs and RNs experience moderate to high levels of subjective stress when performing CE. One-third of the survey participants were at risk of developing PTSD.

The impact of shared decision making with patient decision aids on the rotavirus vaccination rate in children: A randomized controlled trial.

Rotavirus vaccination reduces the incidence and severity of acute gastroenteritis due to rotavirus infection. However, because of a lack of understanding and private payment for the rotavirus vaccine, the rotavirus vaccination rate is still low in some countries. We intended to assess the impact of shared decision-making (SDM) with the assistance of patient decision aids (PDAs) on the rotavirus vaccination rate, and the knowledge, confidence, and congruence of value among baby's parents when decision-making. The study was a two-group, outcome assessor-blind, randomized, controlled trial. The families of 1-month-old infants for routine vaccination were enrolled; they were divided randomly into non-SDM and SDM groups. The influence of SDM on the acceptance of rotavirus vaccination was assessed when their infants were 2 months old. Outcome measures were decisional conflict, decision-making difficulties, and rotavirus vaccine knowledge, and the overall rotavirus vaccination rate. The study enrolled 180 participants. SDM, parents' education level, and rotavirus vaccination of a previous child were variables that influenced acceptance of rotavirus vaccination. The SDM group scored significantly higher for understanding the information on the oral rotavirus vaccine than the non-SDM group, which helped them to decide whether to vaccinate the baby against rotavirus. The rotavirus vaccination rate was 16.7% higher in the SDM group than the non-SDM group. SDM assisted with PDAs gives more information and helps infants' families understand what they need, reduces their decision conflict, and increases their baby's vaccination against rotavirus, which promotes public health. The clinical trial is registered at ClinicalTrials.gov (NCT03804489).

Circadian control of mRNA polyadenylation dynamics regulates rhythmic protein expression.

Poly(A) tails are 3' modifications of eukaryotic mRNAs that are important in the control of translation and mRNA stability. We identified hundreds of mouse liver mRNAs that exhibit robust circadian rhythms in the length of their poly(A) tails. Approximately 80% of these are primarily the result of nuclear adenylation coupled with rhythmic transcription. However, unique decay kinetics distinguish these mRNAs from other mRNAs that are transcribed rhythmically but do not exhibit poly(A) tail rhythms. The remaining 20% are uncoupled from transcription and exhibit poly(A) tail rhythms even though the steady-state mRNA levels are not rhythmic. These are under the control of rhythmic cytoplasmic polyadenylation, regulated at least in some cases by cytoplasmic polyadenylation element-binding proteins (CPEBs). Importantly, we found that the rhythmicity in poly(A) tail length is closely correlated with rhythmic protein expression, with a several-hour delay between the time of longest tail and the time of highest protein level. Our study demonstrates that the circadian clock regulates the dynamic polyadenylation status of mRNAs, which can result in rhythmic protein expression independent of the steady-state levels of the message.

Silicone Hydrogel and Rigid Gas-Permeable Scleral Lens Tear Exchange.

OBJECTIVES: To quantify tear elimination rate (ER) underneath silicone hydrogel (Si-Hy) and scleral gas permeable (GP) contact lenses (CLs). METHODS: Subjects successfully using either well-fitting soft Si-Hy CLs or scleral GP CLs were recruited. Most scleral GP CL wearers had irregular corneas (e.g., keratoconus). An objective fluorometer measured decay of fluorescein isothiocyanate dextran dye signal (70 kD MW) from which the tear ER in %/min was calculated. For GP scleral lenses, the ER was determined for both the initial settling period and the 30- to 60-min period, and without lenses. All ERs were calculated from 5 to 30 min to avoid reflex tearing effects. RESULTS: Fourteen soft Si-Hy CL and 12 scleral GP CL wearers completed the study. The ER for the scleral GP CL wearers averaged 0.57 (±0.6) %/min for the 0- to 30-min and 0.42 (±0.5) %/min for the 30- to 60-min period (P=0.515). Non-CL wear tear ER in these same subjects averaged 34.17 (±15.9) %/min and was significantly different versus both scleral GP wear periods (both P values <0.001). The ER for the soft Si-Hy CL wearers, 5 to 30 min, averaged 6.09 (±2.8) %/min. CONCLUSIONS: Our data demonstrate significantly less ER in well-fit scleral GP CL wearers compared with soft Si-Hy CL wearers for both the settling and longer wear periods (both P values <0.001). Moreover, slightly greater tear exchange was observed during the scleral GP CL settling period than later, which may reflect a change over time in tear vault thickness.

Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.

PURPOSE: The aim of this study was to determine the clinical and molecular characteristics of 2,079 patients who underwent hereditary cancer multigene panel testing. METHODS: Panels included comprehensive analysis of 14-22 cancer susceptibility genes (BRCA1 and BRCA2 not included), depending on the panel ordered (BreastNext, OvaNext, ColoNext, or CancerNext). Next-generation sequencing and deletion/duplication analyses were performed for all genes except EPCAM (deletion/duplication analysis only). Clinical histories of ColoNext patients harboring mutations in genes with well-established diagnostic criteria were assessed to determine whether diagnostic/testing criteria were met. RESULTS: Positive rates were defined as the proportion of patients with a pathogenic mutation/likely pathogenic variant(s) and were as follows: 7.4% for BreastNext, 7.2% for OvaNext, 9.2% for ColoNext, and 9.6% for CancerNext. Inconclusive results were found in 19.8% of BreastNext, 25.6% of OvaNext, 15.1% of ColoNext, and 23.5% of CancerNext tests. Based on information submitted by clinicians, 30% of ColoNext patients with mutations in genes with well-established diagnostic criteria did not meet corresponding criteria. CONCLUSION: Our data point to an important role for targeted multigene panels in diagnosing hereditary cancer predisposition, particularly for patients with clinical histories spanning several possible diagnoses and for patients with suspicious clinical histories not meeting diagnostic criteria for a specific hereditary cancer syndrome.

Protocol for quantifying stem-cell-derived cardiomyocyte maturity using transcriptomic entropy score.

The inability to quantify cardiomyocyte (CM) maturation remains a significant barrier to evaluating the effects of ongoing efforts to produce adult-like CMs from pluripotent stem cells (PSCs). Here, we present a protocol to quantify stem-cell-derived CM maturity using a single-cell RNA sequencing-based metric "entropy score." We describe steps for generating an entropy score using customized R code. This tool can be used to quantify maturation levels of PSC-CMs and potentially other cell types. For complete details on the use and execution of this protocol, please refer to Kannan et al.1.

Paternal DDT exposure induces sex-specific programming of fetal growth, placenta development and offspring's health phenotypes in a mouse model.

Mounting evidence suggests that environmentally induced epigenetic inheritance occurs in mammals and that traits in the progeny can be shaped by parental environmental experiences. Epidemiological studies link parental exposure to environmental toxicants, such as the pesticide DDT, to health phenotypes in the progeny, including low birth and increased risk of chronic diseases later in life. Here, we show that the progeny of male mice exposed to DDT in the pre-conception period are born smaller and exhibit sexual dimorphism in metabolic function, with male, but not female, offspring developing severe glucose intolerance compared to controls. These phenotypes in DDT offspring were linked to reduced fetal growth and placenta size as well as placenta-specific reduction of glycogen levels and the nutrient sensor and epigenetic regulator OGT, with more pronounced phenotypes observed in male placentas. However, placenta-specific genetic reduction of OGT only partially replicates the metabolic phenotype observed in offspring of DDT-exposed males. Our findings reveal a role for paternal pre-conception environmental experiences in shaping placenta development and in fetal growth restriction. While many questions remain, our data raise the tantalizing possibility that placenta programming could be a mediator of environmentally induced intergenerational epigenetic inheritance of phenotypes and needs to be further evaluated.

Factors associated with practice readiness among newly qualified nurses in their first two years of practice.

BACKGROUND: Newly graduated nurses undergo stress and role adjustment as they transition into practice during the first year and continue to struggle beyond the first year. Determining their practice readiness can aid in the development of interventions to facilitate workplace readiness for nurses in their first two years entering the nursing profession. OBJECTIVES: To examine (i) extent of practice readiness of new nurses in their role; and (ii) associations between nurses' practice readiness and demographic and occupational variables, and reasons for choosing nursing profession. DESIGN: A cross-sectional study. SETTINGS AND PARTICIPANTS: A total of 445 registered nurses who graduated within the last two years and working in an academic medical centre in Singapore. METHODS: Participants completed an online questionnaire with questions from Casey-Fink Readiness for Practice Survey and questions related to key competencies for future practice. RESULTS: More than half (57.5 %) identified at least three skills and procedures which they were uncomfortable performing independently as they transition into the clinical practice, including: (i) responding to emergency (ii) tracheostomy care; and (iii) chest tube care. The top three reasons for choosing nursing as a career were: (i) nursing is a stable industry (54.2 %); (ii) I want to help people (52.1 %); and (iii) able to work anywhere in the world (44.3 %). Nurses were most concerned with areas of trials and tribulations (42.5 %) and clinical competency (36.6 %). When compared to nurses in their first-year post-graduation, those working in their second year reported more confidence in the ability to problem solve (p = 0.003), care for a person who is dying (p = 0.004), and less difficulties in prioritizing care needs (p = 0.04). They also perceived themselves as a good problem solver (p = 0.03). CONCLUSIONS: It is critical to continue supporting nurses' practice readiness beyond their first year of practice in their confidence and development of skills of higher complexity.

Palliative Ventilator Withdrawal Practices in an Inpatient Hospice Unit.

BACKGROUND: Palliative ventilator withdrawal (PVW) involves removal of mechanical ventilation in patients not expected to survive to allow a peaceful death. This process traditionally occurs in Intensive Care Units (ICU) and recently has evolved to occur in Inpatient Hospice and Palliative Care Units (IPU). OBJECTIVES: To describe the process and response of patients undergoing PVW in an IPU setting. METHODS: This is a longitudinal observational cohort study of adult patients who underwent PVW in an IPU from January 2021 through March 2022. RESULTS: Among 25 enrolled subjects, median age was 68 (IQR 62.5-76.5) years and 14 (56%) were females. Median time from PVW to death was 16.8 (IQR 2.6-100) hours. A registered nurse and attending physician were present in all the cases, while a respiratory therapist was present in 20 (80%) and chaplain in 9 (36%) of the cases. Before PVW, opioids and benzodiazepines were administered to 24 (96%) patients. Post PVW, respiratory distress was noted among 16 (64%) patients and medication was given to 15 (60%) patients for respiratory distress. There was a significant association between the presence of respiratory distress and administration of medication within 30 minutes after PVW (P = .009). The rituals performed during PVW were reciting prayers for 11 (44%), playing music for 8 (32%), and observing silence for 6 (24%) of the patients. CONCLUSION: This study describes the PVW practices in an IPU setting where a multidisciplinary team was present during PVW for most of the cases and two-third of the patients undergoing PVW experienced respiratory distress immediately after PVW.

Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes.

A limitation in the application of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) is the failure of these cells to achieve full functional maturity. The mechanisms by which directed differentiation differs from endogenous development, leading to consequent PSC-CM maturation arrest, remain unclear. Here, we generate a single-cell RNA sequencing (scRNA-seq) reference of mouse in vivo CM maturation with extensive sampling of previously difficult-to-isolate perinatal time periods. We subsequently generate isogenic embryonic stem cells to create an in vitro scRNA-seq reference of PSC-CM-directed differentiation. Through trajectory reconstruction, we identify an endogenous perinatal maturation program that is poorly recapitulated in vitro. By comparison with published human datasets, we identify a network of nine transcription factors (TFs) whose targets are consistently dysregulated in PSC-CMs across species. Notably, these TFs are only partially activated in common ex vivo approaches to engineer PSC-CM maturation. Our study can be leveraged toward improving the clinical viability of PSC-CMs.

Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model.

DNA sequence accounts for the majority of disease heritability, including cancer. Yet, not all familial cancer cases can be explained by genetic factors. It is becoming clear that environmentally induced epigenetic inheritance occurs and that the progeny's traits can be shaped by parental environmental experiences. In humans, epidemiological studies have implicated environmental toxicants, such as the pesticide DDT, in intergenerational cancer development, including breast and childhood tumors. Here, we show that the female progeny of males exposed to DDT in the pre-conception period have higher susceptibility to developing aggressive tumors in mouse models of breast cancer. Sperm of DDT-exposed males exhibited distinct patterns of small non-coding RNAs, with an increase in miRNAs and a specific surge in miRNA-10b levels. Remarkably, embryonic injection of the entire sperm RNA load of DDT-exposed males, or synthetic miRNA-10b, recapitulated the tumor phenotypes observed in DDT offspring. Mechanistically, miR-10b injection altered the transcriptional profile in early embryos with enrichment of genes associated with cell differentiation, tissue and immune system development. In adult DDT-derived progeny, transcriptional and protein analysis of mammary tumors revealed alterations in stromal and in immune system compartments. Our findings reveal a causal role for sperm RNAs in environmentally induced inheritance of cancer predisposition and, if confirmed in humans, this could help partially explain some of the "missing heritability" of breast, and other, malignancies.