DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs

Biomechanical changes in the tumor microenvironment influence tumor progression and metastases. Collagen content and fiber organization within the tumor stroma are major contributors to biomechanical changes (e., tumor stiffness) and correlated with tumor aggressiveness and outcome. What signals and in what cells control collagen organization within the tumors, and how, is not fully understood. We show in mouse breast tumors that the action of the collagen receptor DDR2 in CAFs controls tumor stiffness by reorganizing collagen fibers specifically at the tumor-stromal boundary. These changes were associated with lung metastases. The action of DDR2 in mouse and human CAFs, and tumors in vivo, was found to influence mechanotransduction by controlling full collagen-binding integrin activation via Rap1-mediated Talin1 and Kindlin2 recruitment. The action of DDR2 in tumor CAFs is thus critical for remodeling collagen fibers at the tumor-stromal boundary to generate a physically permissive tumor microenvironment for tumor cell invasion and metastases

Multiple Overimputation to Address Missing Data and Measurement Error: Application to HIV Treatment During Pregnancy and Pregnancy Outcomes

Investigations of the association of combination antiretroviral therapy (ART) with pregnancy outcomes often rely on routinely collected clinical data, which are prone to missing data and measurement error. Measurement error in gestational age may bias the relationship between combination ART and gestational age-based outcomes

Antiretroviral Adherence Following Prison Release in a Randomized Trial of the imPACT Intervention to Maintain Suppression of HIV Viremia

Many people living with HIV (PLWH) pass through correctional facilities each year, a large proportion of whom do not maintain viral suppression following release. We examined the effects of imPACT, an intervention designed to promote post-release viral suppression, on antiretroviral therapy (ART) adherence. PLWH awaiting release from prisons in two southern states were randomized to imPACT (consisting of motivational interviewing, care linkage coordination, and text message medication reminders) versus standard care (SC). ART adherence, measured by unannounced monthly telephone pill counts, was compared between study arms over 6 months post-release. Of 381 participants eligible for post-release follow-up, 302 (79%) completed ≥ 1 of 6 possible pill counts (median: 4; IQR 1–6). Average adherence over follow-up was 80.3% (95% CI 77.5, 83.1) and 81.0% (78.3, 83.6) of expected doses taken in the imPACT and SC arms, respectively. There was no difference between arms when accounting for missing data using multiple imputation (mean difference = − 0.2 percentage points [− 3.7, 3.3]), controlling for study site and week of follow-up. Of the 936 (40.9%) pill counts that were missed, 212 (22.7%) were due to re-incarceration. Those who missed pill counts for any reason were more likely to be unsuppressed, suggesting that they had lower adherence. However, missingness was balanced between arms. Among PLWH released from prison, ART adherence averaged > 80% in both study arms over 6 months—a level higher than seen with most other chronic diseases. However, missing data may have led to an overestimate of adherence. Factors independent of the intervention influence ART adherence in this population and should be identified to inform future targeted interventions

A risk score to identify HIV-infected women most likely to become lost to follow-up in the postpartum period

Access to lifelong combination antiretroviral therapy (cART) is expanding among HIV-infected pregnant and breastfeeding women throughout sub-Saharan Africa. For this strategy to meaningfully improve maternal HIV outcomes, retention in HIV care is essential. We developed a risk score to identify women with high likelihood of loss to follow-up (LTFU) at 6 months postpartum from HIV care, using data from public health facilities in Lusaka, Zambia. LTFU was defined as not presenting for HIV care within 60 days of the last scheduled appointment. We used logistic regression to assess demographic, obstetric, and HIV predictors of LTFU and to develop a simple risk score. Sensitivity and specificity were assessed at each risk score cut-point. Among 2,029 pregnant women initiating cART between 2009 and 2011, 507 (25%) were LTFU by 6 months postpartum. Parity, education, employment status, WHO clinical stage, duration of cART during pregnancy, and number of antenatal care visits were associated with LTFU (p-value<0.10). A risk score cut-point of 11 (42nd percentile) had 85% sensitivity (95% CI 82%, 88%) and 22% specificity (95% CI 20%, 24%) to detect women LTFU and would exclude 20% of women from a retention intervention. A risk score cut-point of 18 (69th percentile) identified the 23% of women with the highest probability of LTFU and had sensitivity 32% (95% CI 28%, 36%) and specificity 80% (95% CI 78%, 82%). A risk score approach may be useful to triage a subset of women most likely to be LTFU for targeted retention interventions

T-BET and EOMES sustain mature human NK cell identity and antitumor function

Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells. Mechanistically, T-BET and EOMES were required for normal NK cell proliferation and persistence in vivo. NK cells lacking T-BET and EOMES also exhibited defective responses to cytokine stimulation. Single-cell RNA-Seq revealed a specific T-box transcriptional program in human NK cells, which was rapidly lost following T-BET and EOMES deletion. Further, T-BET- and EOMES-deleted CD56bright NK cells acquired an innate lymphoid cell precursor-like (ILCP-like) profile with increased expression of the ILC-3-associated TFs RORC and AHR, revealing a role for T-box TFs in maintaining mature NK cell phenotypes and an unexpected role of suppressing alternative ILC lineages. Our study reveals the critical importance of sustained EOMES and T-BET expression to orchestrate mature NK cell function and identity

DNA Ploidy of Basal Cell Carcinoma Determined by Image Cytometry of Fresh Smears

Image analysis of nuclear DNA content (DNA ploidy) was performed on smears of basal cell carcinoma (BCC) obtained during Mohs microscopically-controlled surgery from 51 tumors. DNA ploidy was compared with histologic growth pattern and the contour of the invading edge. There was a statistically significantly increased frequency of DNA aneuploidy in smears from BCC exhibiting partial or total diffuse (infiltrative and superficial multicentric) growth patterns (80%; 32 of 40) as compared to solely circumscribed growth patterns (0%; 0 of 11) (p\u3c 0.001)