Heavy Metals in Breast Implant Capsules and Breast Tissue: Findings from the Systemic Symptoms in Women-Biospecimen Analysis Study: Part 2.

BACKGROUND: Breast Implant Illness (BII), as described in recent medical literature and by social media, describes a range of symptoms in patients with breast implants for which there are no physical findings or laboratory results that explain their symptoms. OBJECTIVES: Part 2 of this study aims to determine whether heavy metals are present in the capsules around saline and silicone implants and if there are statistical differences in the type or level of these metals between women with or without symptoms. Demographic data was collected to investigate potential alternate sources of metals: inhaled, absorbed, or ingested. METHODS: A prospective, blinded study enrolled 150 consecutive subjects divided equally into in three cohorts: (A) women with systemic symptoms they attribute to their implants who requested implant removal, (B) women with breast implants requesting removal or exchange who do not have symptoms they attribute to their implants, and (C) women undergoing cosmetic mastopexy who have never had any implanted medical device. Capsule tissue was removed from Cohort A and B for analysis of 22 heavy metals. Additionally, breast tissue was obtained from a control group with no previous exposure to any implanted medical device. RESULTS: The study was performed between 2019-2021. Heavy metal content was compared between the capsule tissue from Cohort A and B. The only statistically significant differences identified in Cohort A were higher levels of arsenic and zinc, and lower levels of cobalt, manganese, silver, and tin. There were no elevated levels or statistically significant differences in the other metals tested between Cohorts A and B. CONCLUSIONS: This study analyzes the metal content in capsules surrounding both saline and silicone breast implants. Heavy metals were also detected in the non-implant control group breast tissue, with some metals at numerically higher levels than either breast implant cohort. Smoking, gluten free diets, dietary supplements, and the presence of tattoos were all identified as statistically significant sources of arsenic and zinc in Cohort A. The risk of heavy metal toxicity should not be used as an indication for total capsulectomy if patients elect to remove their breast implants.

Impact of Capsulectomy Type on Post-Explantation Systemic Symptom Improvement: Findings From the ASERF Systemic Symptoms in Women-Biospecimen Analysis Study: Part 1.

BACKGROUND: Breast Implant Illness (BII) is a term used to describe a variety of symptoms by patients with breast implants for which there are no abnormal physical or laboratory findings to explain their symptoms. There currently exists a difference of opinion among clinicians and patients concerning the diagnosis and treatment of patients self-reporting BII. OBJECTIVES: The first aim of this study was to determine if there is a valid indication for "en bloc" capsulectomy in patients self-reporting BII and if the type of capsulectomy performed alters long-term symptom improvement. The second goal was to identify any clinical laboratory differences between the cohorts. This study was funded by the Aesthetic Surgery Education and Research Foundation (ASERF). METHODS: A prospective blinded study enrolled 150 consecutive subjects divided equally into 3 cohorts: (A) women with systemic symptoms they attribute to their implants who requested implant removal; (B) women with breast implants requesting removal or exchange who do not have symptoms they attribute to their implants; and (C) women undergoing cosmetic mastopexy who have never had any implanted medical device. The subject's baseline demographic data and a systemic symptoms survey, including PROMIS validated questionnaires, was obtained before surgery and at 3-6 weeks, 6 months, and 1 year. Blood was collected from all 3 cohorts and implant capsules were collected from Cohorts A and B. RESULTS: 150 patients were enrolled between 2019-2021. Follow-up at 3-6 weeks for all 3 cohorts was between 98%-100%, 78%-98% at 6-months, and 1 year data is currently at 80%. The type of capsulectomy; intact total, total, or partial all showed similar symptom improvement with no statistical difference in the reduction of symptoms based on the type of capsulectomy. CONCLUSIONS: This study addresses one of the most discussed questions by plastic surgeons, patients, their advocates, and social media. The findings show that patients who self-report BII demonstrate a statistically significant improvement in their symptoms after explantation and that this improvement persists for at least 6 months. This improvement in self-reported systemic symptoms was seen regardless of the type of capsulectomy performed.

Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy.

Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b(+)F4/80(+) tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b(+)Gr-1(lo)Ly6C(hi) mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti-VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.

Spinodal decomposition of mono- to few-layer graphene on Ni substrates at low temperature.

Mono to few-layer graphene were prepared on pre-annealed polycrystalline nickel substrates by chemical vapor deposition at a relatively low temperature of 800 degrees C using fast cooling rate. It was observed that the reduced solubility of Carbon in Ni at low temperature and an optimum gas mixing ratio (CH4:H2 = 60/80 (sccm)) can be used to synthesize mano-layer graphene that covers about 100 microm2 area. The number of graphene layers strongly depends upon the hydrogen and methane flow rates. An increase in the methane flow is found to increase the growth density of the single-layer graphene. The number of graphene layers was identified from micro-Raman spectra. The thinnest areas containing mono-layer graphene formed at small Ni grains surrounded by large Ni Grains can be explained in terms of Spinodal decomposition. Scanning tunneling microscopy observations of the graphene samples indicate that the graphene structure exhibits no defects, and extremely symmetry hexagon carbon at flat graphene surface is observed.

Diamond LED substrate and novel quantum dots.

Nitride LED (e.g., GaN) has become the mainstream of blue light source. The blue light can be converted to white light by exciting a phosphor (e.g., Nichia's YAG or Osram's TAG) with the complementary yellow emission. However, GaN is typically deposited on sapphire (Al2O3) substrates formed by crystal pulling or hexagonal (e.g., 4 H or 6 H) SiC wafers condensed from SiC vapor. In either case, the nitride lattice is ridden (e.g., 10(9)/cm2) with dislocations. The high dislocation density with sapphire is due to the large (>13%) lattice mismatch; and with hexagonal SiC, because of intrinsic defects. Cubic (beta) SiC may be deposited epitaxially using a CVD reactor onto silicon wafer by diffusing the interface and by chemical gradation. A reactive echant (e.g., hydrogen or fluorine) can be introduced periodically to gasify mis-aligned atoms. In this case, large single crystal wafers would be available for the manufacture of high bright LED with superb electro-optical efficiency. The SiC wafer may be coated with diamond film that can eliminate heat in real time. As a result of lower temperature, the nitride LED can be brighter and it will last longer. The blue light of GaN LED formed on SiC on Diamond (SiCON) LED may also be scattered by using novel quantum dots (e.g., 33 atom pairs of CdSe) to form a broad yellow light that blend in with the original blue light to form sunlight-like white light. This would be the ideal source for general illumination (e.g., for indoor) or backlighting (e.g., for LCD).

HER-2/neu expression in locally advanced breast carcinomas: pre-and post-neoadjuvant chemotherapy.

Clinical studies have shown a correlation of HER-2/neu amplification/over-expression and favorable response to neoadjuvant chemotherapy and anti-HER-2/neu antibody treatment. However, contradictory findings also have been reported. Some tumors may develop resistance to neoadjuvant chemotherapy after an initial period of sensitivity. Our study attempts to evaluate the effects of neoadjuvant chemotherapy on HER-2/neu status in locally advanced breast cancer. Thirty-nine patients with locally advanced breast cancers established by core needle biopsy received neoadjuvant chemotherapy and were compared with 60 patients with breast cancers who did not receive neoadjuvant chemotherapy. IHC for HER-2/neu was performed on paraffin sections of the core biopsy before treatment and the excised specimen following chemotherapy and scored as Negative (0-1+), 2+ and 3+. The results of the study and the controls were compared and analyzed using Fisher's exact test. HER-2/neu IHC scores decreased in 28.5% (15/39) of patients receiving neo-adjuvant chemotherapy compared to 11.7% (7/60) of patients in the control (p < 0.013). HER-2/neu IHC status changed from strongly positive to negative (3+ to 0) in five of 39 (12.5%) in the study group and in 2 of 60 (3.3%) in control group (p = 0.104). For patients receiving neoadjuvant chemotherapy in whom the tumor becomes refractory to chemotherapy or recurs, repeat testing for HER-2/neu status may be necessary. Elimination of HER-2/neu positive tumor cells may account for the changes in the IHC scores and the development of resistance to neoadjuvant chemotherapy.

CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy.

Growing evidence suggests that tumor-associated macrophages (TAM) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix-remodeling, and immunosuppression. In this study, prostate cancer under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to prostate cancer disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF1 or CSF1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF1 signaling through its receptor, CSF1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared with ABT alone.

CD28 co-stimulation regulates the effect of transforming growth factor-beta1 on the proliferation of naïve CD4+ T cells.

Transforming growth factor-beta1 (TGF-beta1) is a critical regulator of T cell responses in vivo. In vitro, TGF-beta1 can either enhance or inhibit T cell proliferative responses, but the relevant factors that determine the T cell response to TGF-beta1 remain obscure. Here, we present evidence that CD28 co-stimulation modifies the effects of TGF-beta1 on T cell proliferation. In the absence of CD28 co-stimulation, TGF-beta1 potently suppressed TCR-stimulated proliferation of naïve T cells. In the presence of CD28 co-stimulation, TGF-beta1 potently inhibited T cell apoptosis and enhanced TCR-stimulated proliferation. A similar effect of CD28 co-stimulation was not observed in memory/effector cells, whose proliferation was enhanced by TGF-beta1, whether co-stimulated or not. We examined the mechanism by which CD28 modulates naïve T cell responses to TGF-beta1. Since CD28 co-stimulation classically is a potent enhancer of interleukin (IL)-2 production, we anticipated observing high IL-2 production from naïve T cells stimulated with anti-CD3/anti-CD28 and TGF-beta1. Surprisingly, however, TGF-beta1 strongly inhibited production of IL-2 from naïve CD4(+) T cells, even when CD28 was engaged. Even though IL-2 levels were strongly suppressed by TGF-beta1 to trace levels, antibody neutralization studies showed that IL-2 is still a basic requirement for the proliferation of anti-CD3/anti-CD28/TGF-beta1-stimulated naïve T cells. These data show that CD28's modulation of T cell responses to TGF-beta1 is not via the production of high levels of IL-2, and suggest that engagement of CD28 may activate additional downstream pathways that modulate the responses of naïve T cells to TGF-beta1.

Targeting polymeric fluorescent nanodiamond-gold/silver multi-functional nanoparticles as a light-transforming hyperthermia reagent for cancer cells.

This work demonstrates a simple route for synthesizing multi-functional fluorescent nanodiamond-gold/silver nanoparticles. The fluorescent nanodiamond is formed by the surface passivation of poly(ethylene glycol) bis(3-aminopropyl) terminated. Urchin-like gold/silver nanoparticles can be obtained via one-pot synthesis, and combined with each other via further thiolation of nanodiamond. The morphology of the nanodiamond-gold/silver nanoparticles thus formed was identified herein by high-resolution transmission electron microscopy, and clarified using diffraction patterns. Fourier transform infrared spectroscopy clearly revealed the surface functionalization of the nanoparticles. The fluorescence of the materials with high photo stability was examined by high power laser irradiation and long-term storage at room temperature. To develop the bio-recognition of fluorescent nanodiamond-gold/silver nanoparticles, pre-modified transferrin was conjugated with the gold/silver nanoparticles, and the specificity and activity were confirmed in vitro using human hepatoma cell line (J5). The cellular uptake analysis that was conducted using flow cytometry and inductively coupled plasma mass spectrometry exhibited that twice as many transferrin-modified nanoparticles as bare nanoparticles were engulfed, revealing the targeting and ease of internalization of the human hepatoma cell. Additionally, the in situ monitoring of photothermal therapeutic behavior reveals that the nanodiamond-gold/silver nanoparticles conjugated with transferrin was more therapeutic than the bare nanodiamond-gold/silver materials, even when exposed to a less energetic laser source. Ultimately, this multi-functional material has great potential for application in simple synthesis. It is non-cytotoxic, supports long-term tracing and can be used in highly efficient photothermal therapy against cancer cells.

Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis.

Lymph node involvement denotes a poor outcome for patients with prostate cancer. Our group, along with others, has shown that initial tumor cell dissemination to regional lymph nodes via lymphatics also promotes systemic metastasis in mouse models. The aim of this study was to investigate the efficacy of suppressive therapies targeting either the angiogenic or lymphangiogenic axis in inhibiting regional lymph node and systemic metastasis in subcutaneous and orthotopic prostate tumor xenografts. Both androgen-dependent and more aggressive androgen-independent prostate tumors were used in our investigations. Interestingly, we observed that the threshold for dissemination is lower in the vascular-rich prostatic microenvironment compared with subcutaneously grafted tumors. Both vascular endothelial growth factor-C (VEGF-C) ligand trap (sVEGFR-3) and antibody directed against VEGFR-3 (mF4-31C1) significantly reduced tumor lymphangiogenesis and metastasis to regional lymph nodes and distal vital organs without influencing tumor growth. Conversely, angiogenic blockade by short hairpin RNA against VEGF or anti-VEGFR-2 antibody (DC101) reduced tumor blood vessel density, significantly delayed tumor growth, and reduced systemic metastasis, although it was ineffective in reducing lymphangiogenesis or nodal metastasis. Collectively, these data clarify the utility of vascular therapeutics in prostate tumor growth and metastasis, particularly in the context of the prostate microenvironment. Our findings highlight the importance of lymphangiogenic therapies in the control of regional lymph node and systemic metastasis.

Analysis of bacterial random motility in a porous medium using magnetic resonance imaging and immunomagnetic labeling.

In this study, we demonstrate the application of immunomagnetic labeling and magnetic resonance imaging (MRI) for the noninvasive visualization of changes in bacterial density distributions as a function of time in a water-saturated porous medium. Magnetite particles (50-60 nm diameter) were attached via a monoclonal antibody to the surface' of Escherichia coli K12 NR50 cells. The cells maintained their motility after labeling, and the presence of the magnetite did not significantly alter cell swimming speed. Diffusive migration for both motile and nonmotile E. coli through a porous medium with a particle-diameter distribution of 250-300 microm was compared. The movement of the nonmotile cells was described by an effective random motility coefficient consistent with Brownian diffusion of a nonmotile colloid. An effective coefficient determined a priori from bacterial motility in an aqueous medium and properties of the porous medium adequately described the movement of the motile cells. The ability to noninvasively visualize bacterial concentrations within an opaque porous medium in real time provides researchers with a powerful tool for studying bacterial transport in porous media. This is important for understanding the impact of bacterial transport on remediation strategies for environmental cleanup of polluted groundwater.