Functionality of bone marrow mesenchymal stromal cells derived from head and neck cancer patients - A FDA-IND enabling study regarding MSC-based treatments for radiation-induced xerostomia.

PURPOSE: Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs [MSC(M)] from HNC patients could be used for the treatment of RT-induced salivary dysfunction. METHODS: An IRB-approved pilot clinical study was undertaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated and cultured. Culture-expanded MSC(M) were stimulated with IFNγ and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. MSC(M) were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology and salivary production were examined. RESULTS: A total of six subjects were enrolled. MSC(M) from all subjects were culture expanded to > 20 million cells in a median of 15.5 days (range 8-20 days). Flow cytometry confirmed that cultured cells from HNC patients were MSC(M). Functional flow cytometry demonstrated that these IFNγ-stimulated MSC(M) acquired an immunosuppressive phenotype. IFNγ-stimulated MSC(M) from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFNγ-stimulated MSC(M) injection after radiation decreased the loss of acinar cells, decreased the formation of fibrosis, and increased salivary production. CONCLUSIONS: MSC (M) from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore IFNγ-stimulated MSC(M) express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous MSC(M) from HNC patients to treat RT-induced salivary dysfunction.

Navigating Unequal Paths: Racial Disparities in the Infertility Journey.

Infertility is one of the most emotionally devastating conditions experienced during the reproductive window. Although not life-threatening, it significantly erodes quality of life for those with the diagnosis. Disturbingly, data demonstrate the existence of profound racial disparities that persist along the entire journey of infertility. Though most of the scientific literature emphasizes disparities in clinical outcomes after infertility treatment, it is important to recognize that these inequities are the downstream effect of a series of distinct challenges encountered by historically marginalized people on their path to parenthood. In this review, we explore the current state of knowledge concerning the inequities at each "step" in the path to overcome infertility challenges and propose solutions to create a future in which reproductive medicine is truly equitable, accessible, and supportive for everyone.

Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): A pilot, first-in-human study of interferon gamma-stimulated marrow mesenchymal stromal cells for treatment of radiation-induced xerostomia.

BACKGROUND AIMS: Xerostomia, or the feeling of dry mouth, is a significant side effect of radiation therapy for patients with head and neck cancer (HNC). Preliminary data suggest that mesenchymal stromal/stem cells (MSCs) can improve salivary function. We performed a first-in-human pilot study of interferon gamma (IFNγ)-stimulated autologous bone marrow-derived MSCs, or MSC(M), for the treatment of radiation-induced xerostomia (RIX). Here we present the primary safety and secondary efficacy endpoints. METHODS: A single-center pilot clinical trial was conducted investigating the safety and tolerability of autologous IFNγ-stimulated MSC(M). The study was conducted under an approved Food and Drug Administration Investigational New Drug application using an institutional review board-approved protocol (NCT04489732). Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated, cultured, stimulated with IFNγ and cryopreserved for later use. Banked cells were thawed and allowed to recover in culture before patients received a single injection of 10 × 106 MSC(M) into the right submandibular gland under ultrasound guidance. The primary objective was determination of safety and tolerability by evaluating dose-limiting toxicity (DLT). A DLT was defined as submandibular pain >5 on a standard 10-point pain scale or any serious adverse event (SAE) within 1 month after injection. Secondary objectives included analysis of efficacy as measured by salivary quantification and using three validated quality of life instruments. Quantitative results are reported as mean and standard deviation. RESULTS: Six patients with radiation-induced xerostomia who had completed radiation at least 2 years previously (average 7.8 years previously) were enrolled in the pilot study. The median age was 71 (61-74) years. Five (83%) patients were male. Five patients (83%) were treated with chemoradiation and one patient (17%) with radiation alone. Grade 1 pain was seen in 50% of patients after submandibular gland injection; all pain resolved within 4 days. No patients reported pain 1 month after injection, with no SAE or other DLTs reported 1 month after injection. The analysis of secondary endpoints demonstrated a trend of increased salivary production. Three patients (50%) had an increase in unstimulated saliva at 1 and 3 months after MSC(M) injection. Quality of life surveys also showed a trend toward improvement. CONCLUSIONS: Injection of autologous IFNγ-stimulated MSC(M) into a singular submandibular gland of patients with RIX is safe and well tolerated in this pilot study. A trend toward an improvement in secondary endpoints of salivary quantity and quality of life was observed. This first-in-human study provides support for further investigation into IFNγ-stimulated MSC(M) injected in both submandibular glands as an innovative approach to treat RIX and improve quality of life for patients with HNC.

Fresh vs. frozen embryo transfer: new approach to minimize the limitations of using national surveillance data for clinical research.

OBJECTIVE: To assess the benefit of frozen vs. fresh elective single embryo transfer using traditional and novel methods of controlling for confounding. DESIGN: Retrospective cohort study using data from the National Assisted Reproductive Technology Surveillance System. SETTING: Not applicable. PATIENT(S): A total of 44,750 women aged 20-35 years undergoing their first lifetime oocyte retrieval and embryo transfer in 2016-2017, who had ≥4 embryos cryopreserved. INTERVENTION(S): Fresh elective single embryo transfer and frozen elective single embryo transfer. MAIN OUTCOME MEASURE(S): The primary outcome was a singleton live birth. Secondary outcomes included rates of total live birth (singleton plus multiple gestations), twin live birth, clinical intrauterine gestation, total pregnancy loss, biochemical pregnancy, and ectopic pregnancy. Outcomes for infants included gestational age at delivery, birth weight, and being small for gestational age. RESULT(S): The eligibility criteria were met by 6,324 fresh and 2,318 frozen cycles. Patients undergoing fresh and frozen transfer had comparable mean age (30.69 [standard deviation {SD} 0.08] years vs. 31.06 [SD 0.08] years) and body mass index (24.76 [SD 0.20] vs. 25.65 [SD 0.15]); however, women in the frozen cohort created more embryos (8.1 [SD 0.12] vs. 6.8 [SD 0.08]). Singleton live birth rates in the fresh vs. frozen groups were 51.4% vs. 48.8% (risk ratio 1.05; 95% confidence interval [CI], 1.00-1.10). After adjustment with a log-linear regression model and propensity score analysis, the difference in singleton live birth rates remained nonsignificant (adjusted risk ratio, 1.05; 95% CI, 0.97-1.14 and 1.02; 95% CI, 0.96-1.08, respectively). A novel dynamical model confirmed inherent fertility (probability of ever achieving a pregnancy) was balanced between groups (odds ratio, 1.23; 95% CI 0.78-1.95]). The per-cycle probability of singleton live birth was not different between groups (odds ratio 1.11 [95% CI 0.94-1.3]). CONCLUSION(S): In this retrospective cohort study of fresh vs. frozen elective single embryo transfer, there was no statistically significant difference in singleton live birth rate after adjustment using log-linear models and propensity score analysis. The successful application of a novel dynamical model, which incorporates multiple assisted reproductive technology cycles from the same woman as a surrogate for inherent fertility, offers a novel and complementary perspective for assessing interventions using national surveillance data.

Duration, recency, and type of hormonal contraceptive use and antimüllerian hormone levels.

OBJECTIVE: To assess whether the duration, recency, or type of hormonal contraceptive used is associated with antimüllerian hormone (AMH) levels, given that the existing literature regarding the association between hormonal contraceptive use and AMH levels is inconsistent. DESIGN: Cross-sectional study. SETTING: Baseline data from the Study of the Environment, Lifestyle and Fibroids Study, a 5-year longitudinal study of African American women. PATIENT(S): The patients were 1,643 African American women aged 23-35 years at the time of blood drawing (2010-2012). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum AMH level was measured by an ultrasensitive enzyme-linked immunosorbent assay. Linear regression models were used to estimate percent differences in mean AMH levels and 95% confidence intervals (CIs) according to use of hormonal contraceptives, with adjustment for potential confounders. RESULT(S): In multivariable-adjusted analyses, current users of hormonal contraceptives had 25.2% lower mean AMH levels than non-users of hormonal contraceptives (95% CI: -35.3%, -13.6%). There was little difference in AMH levels between former users and non-users of hormonal contraceptives (-4.4%; 95% CI: -16.3%, 9.0%). AMH levels were not appreciably associated with cumulative duration of use among former users or time since last use among non-current users. Current users of combined oral contraceptives (-24.0%; 95% CI: -36.6%, -8.9%), vaginal ring (-64.8%; 95% CI: -75.4%, -49.6%), and depot medroxyprogesterone acetate (-26.7%; 95% CI: -41.0%, -8.9%) had lower mean AMH levels than non-users. CONCLUSION(S): The present data suggest that AMH levels are significantly lower among current users of most forms of hormonal contraceptives, but that the suppressive effect of hormonal contraceptives on AMH levels is reversible.

Lifestyle modifications alone or combined with hormonal contraceptives improve sexual dysfunction in women with polycystic ovary syndrome.

OBJECTIVE: To describe the prevalence of female sexual dysfunction in a well-defined polycystic ovary syndrome (PCOS) population, and to assess the impact of common PCOS treatments on sexual function. DESIGN: Secondary analysis of a randomized controlled trial, oral contraceptive pills and weight loss in PCOS. SETTING: Two academic medical centers. PATIENTS: Women with PCOS (N = 114) defined by the Rotterdam criteria. INTERVENTIONS: Continuous oral contraceptive pill (OCP) or intensive lifestyle modification (Lifestyle) or the combination (Combined) for 16 weeks. MAIN OUTCOME MEASURES: Change in Female Sexual Function Index (FSFI) and Female Sexual Distress Scale-Revised (FSDS-R) scores after 16 weeks. RESULTS: There was no change in total FSFI or FSDS-R score in any treatment group; however, an increase in the FSFI desire domain subscore was observed in the Lifestyle and Combined treatments, indicating improved sexual desire over the 16-week period. Overall, 33 participants (28.9%) met criteria for sexual dysfunction by FSFI criteria (baseline score ≤26.55). Among this group, FSFI score improved after 16 weeks of Lifestyle and Combined treatments. There was no change in prevalence of sexual dysfunction in treatment groups at 16 weeks. Use of OCPs did not alter FSFI scores. CONCLUSION(S): Female sexual dysfunction is highly prevalent among women with PCOS. Our findings suggest that common treatments for PCOS, including intensive lifestyle modification and the combination of intensive lifestyle modification and OCPs, have the potential to improve sexual function in these women; the mechanism for these improvements is likely multifactorial. CLINICAL TRIAL REGISTRATION NUMBER: NCT00704912.

Nitrate is an important nitrogen source for Arctic tundra plants.

Plant nitrogen (N) use is a key component of the N cycle in terrestrial ecosystems. The supply of N to plants affects community species composition and ecosystem processes such as photosynthesis and carbon (C) accumulation. However, the availabilities and relative importance of different N forms to plants are not well understood. While nitrate (NO3-) is a major N form used by plants worldwide, it is discounted as a N source for Arctic tundra plants because of extremely low NO3- concentrations in Arctic tundra soils, undetectable soil nitrification, and plant-tissue NO3- that is typically below detection limits. Here we reexamine NO3- use by tundra plants using a sensitive denitrifier method to analyze plant-tissue NO3- Soil-derived NO3- was detected in tundra plant tissues, and tundra plants took up soil NO3- at comparable rates to plants from relatively NO3--rich ecosystems in other biomes. Nitrate assimilation determined by 15N enrichments of leaf NO3- relative to soil NO3- accounted for 4 to 52% (as estimated by a Bayesian isotope-mixing model) of species-specific total leaf N of Alaskan tundra plants. Our finding that in situ soil NO3- availability for tundra plants is high has important implications for Arctic ecosystems, not only in determining species compositions, but also in determining the loss of N from soils via leaching and denitrification. Plant N uptake and soil N losses can strongly influence C uptake and accumulation in tundra soils. Accordingly, this evidence of NO3- availability in tundra soils is crucial for predicting C storage in tundra.

Nonnative forest insects and pathogens in the United States: Impacts and policy options.

We review and synthesize information on invasions of nonnative forest insects and diseases in the United States, including their ecological and economic impacts, pathways of arrival, distribution within the United States, and policy options for reducing future invasions. Nonnative insects have accumulated in United States forests at a rate of ~2.5 per yr over the last 150 yr. Currently the two major pathways of introduction are importation of live plants and wood packing material such as pallets and crates. Introduced insects and diseases occur in forests and cities throughout the United States, and the problem is particularly severe in the Northeast and Upper Midwest. Nonnative forest pests are the only disturbance agent that has effectively eliminated entire tree species or genera from United States forests within decades. The resulting shift in forest structure and species composition alters ecosystem functions such as productivity, nutrient cycling, and wildlife habitat. In urban and suburban areas, loss of trees from streets, yards, and parks affects aesthetics, property values, shading, stormwater runoff, and human health. The economic damage from nonnative pests is not yet fully known, but is likely in the billions of dollars per year, with the majority of this economic burden borne by municipalities and residential property owners. Current policies for preventing introductions are having positive effects but are insufficient to reduce the influx of pests in the face of burgeoning global trade. Options are available to strengthen the defenses against pest arrival and establishment, including measures taken in the exporting country prior to shipment, measures to ensure clean shipments of plants and wood products, inspections at ports of entry, and post-entry measures such as quarantines, surveillance, and eradication programs. Improved data collection procedures for inspections, greater data accessibility, and better reporting would support better evaluation of policy effectiveness. Lack of additional action places the nation, local municipalities, and property owners at high risk of further damaging and costly invasions. Adopting stronger policies to reduce establishments of new forest insects and diseases would shift the major costs of control to the source and alleviate the economic burden now borne by homeowners and municipalities.

Soil processes drive seasonal variation in retention of 15N tracers in a deciduous forest catchment.

Seasonal patterns of stream nitrate concentration have long been interpreted as demonstrating the central role of plant uptake in regulating stream nitrogen loss from forested catchments. Soil processes are rarely considered as important drivers of these patterns. We examined seasonal variation in N retention in a deciduous forest using three whole-ecosystem 15N tracer additions: in late April (post-snowmelt, pre-leaf-out), late July (mid-growing- season), and late October (end of leaf-fall). We expected that plant 15N uptake would peak in late spring and midsummer, that immobilization in surface litter and soil would peak the following autumn leaf-fall, and that leaching losses would vary inversely with 15N retention. Similar to most other 15N tracer studies, we found that litter and soils dominated ecosystem retention of added 15N. However, 15N recovery in detrital pools varied tremendously by season, with > 90% retention in spring and autumn and sharply reduced 15N retention in late summer. During spring, over half of the 15N retained in soil occurred within one day in the heavy (mineral-associated) soil fraction. During summer, a large decrease in 15N retention one week after addition coincided with increased losses of 15NO3- to soil leachate and seasonal increases in soil and stream NO3- concentrations, although leaching accounted for only a small fraction of the lost 15N (< 0.2%). Uptake of 15N into roots did not vary by season and accounted for < 4% of each tracer addition. Denitrification or other processes that lead to N gas loss may have consumed the rest. These measurements of 15N movement provide strong evidence for the dominant role of soil processes in regulating seasonal N retention and losses in this catchment and perhaps others with similar soils.