RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to interferon/STAT1 pro-apoptosis signaling.

BACKGROUND: RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM+ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. METHODS: We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm-/- mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm-loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. RESULTS: Rhamm-loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm-loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm-/- primary tumor clones that are enriched in lung metastases. Rhamm-/- tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM+ve tumor cells to a significantly greater extent than RHAMM-ve comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. CONCLUSION: RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.

Ab Externo SIBS Microshunt with Mitomycin C for Open-Angle Glaucoma: Three-Year Results as a Primary Surgical Intervention.

PURPOSE: To determine the effectiveness, risk factors for surgical failure, and adverse events in a large cohort of patients receiving stand-alone ab externo poly(styrene-block-isobutylene-block-styrene) (SIBS) microshunt implantation with mitomycin C (MMC) over 3 years of follow-up. DESIGN: Retrospective, interventional case series. PARTICIPANTS: Glaucomatous eyes on maximally tolerated medical therapy with no previous subconjunctival glaucoma surgery. METHODS: Records of eyes that underwent ab externo SIBS microshunt with MMC between July 2015 and November 2017 were reviewed. Data from all follow-up visits were utilized and included intraocular pressure (IOP), medication use, postoperative interventions, complications, and reoperations. MAIN OUTCOME MEASURES: The primary outcome was proportion of eyes at 3 years with (1) no 2 consecutive IOPs > 17 mmHg (or < 6 mmHg with > 2 lines of vision loss from baseline); (2) ≥ 20% reduction from baseline IOP; and (3) using no glaucoma medications (complete success). Secondary outcomes included 14 and 21 mmHg upper IOP thresholds with and without ≥ 20% IOP reduction from baseline, qualified success (with glaucoma medications), risk factors for failure, median IOP/medications, postoperative interventions, complications, and reoperations. RESULTS: One hundred fifty-two eyes from 135 patients were included. Complete and qualified success was achieved in 55.6% and 74.8% of eyes, respectively. Time to first glaucoma medication use was a median of 16.9 (interquartile range [IQR], 12.1-34.1) months; however, 59.4% of eyes remained medication free at 3 years. Significant risk factors for failure included receiving < 0.4 mg/ml of MMC (adjusted hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.44-4.05) and baseline IOP < 21 mmHg (adjusted HR, 1.79; 95% CI, 1.03-3.13). The most common complications were choroidal detachment, hyphema, and anterior chamber shallowing, occurring in 7%, 5%, and 5% of eyes, respectively. The needling rate was 15.1%, with significantly higher frequency for baseline IOP > 21 mmHg (HR, 3.21; 95% CI, 1.38-7.48). Revisions occurred in 7% of eyes and reoperations in 2.6%. Eyes receiving < 0.4 mg/ml of MMC underwent more revisions (odds ratio, 4.9; 95% CI, 1.3-18.3). CONCLUSIONS: Three-year follow-up data from this large cohort continues to support promising rates of qualified and complete success, with decreased medication burden postoperatively and few postoperative complications and interventions. Comparisons to other filtering surgeries will further facilitate integration of the SIBS microshunt into the surgical treatment paradigm. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Hyaluronan modulates growth factor induced mammary gland branching in a size dependent manner.

Mammary gland morphogenesis begins during fetal development but expansion of the mammary tree occurs postnatally in response to hormones, growth factors and extracellular matrix. Hyaluronan (HA) is an extracellular matrix polysaccharide that has been shown to modulate growth factor-induced branching in culture. Neither the physiological relevance of HA to mammary gland morphogenesis nor the role that HA receptors play in these responses are currently well understood. We show that HA synthase (HAS2) is expressed in both ductal epithelia and stromal cells but HA primarily accumulates in the stroma. HA accumulation and expression of the HA receptors CD44 and RHAMM are highest during gestation when gland remodeling, lateral branch infilling and lobulo-alveoli formation is active. Molecular weight analyses show that approximately 98% of HA at all stages of morphogenesis is >300kDa. Low levels of 7-114kDa HA fragments are also detected and in particular the accumulation of 7-21kDa HA fragments are significantly higher during gestation than other morphogenetic stages (p<0.05). Using these in vivo results as a guide, in culture analyses of mammary epithelial cell lines (EpH4 and NMuMG) were performed to determine the roles of high molecular weight, 7-21kDa (10kDa MWavg) and HA receptors in EGF-induced branching morphogenesis. Results of these assays show that while HA synthesis is required for branching and 10kDa HA fragments strongly stimulate branching, the activity of HA decreases with increasing molecular weight and 500kDa HA strongly inhibits this morphogenetic process. The response to 10kDa HA requires RHAMM function and genetic deletion of RHAMM transiently blunts lateral branching in vivo. Collectively, these results reveal distinct roles for HA polymer size in modulating growth factor induced mammary gland branching and implicates these polymers in both the expansion and sculpting of the mammary tree during gestation.

Outcomes of Wound Dehiscence Post-Penetrating Keratoplasty.

PURPOSE: Penetrating keratoplasties (PKs) carry a lifetime risk of developing wound dehiscence, which can lead to severe consequences to vision. To better understand the risk, we analyzed the characteristics and outcomes of a series of patients with wound dehiscence post-PK. METHODS: Data were collected retrospectively on 31 eyes from 30 patients with a history of wound dehiscence repair post-PK between January 1, 2009, and April 30, 2014, and followed up at the Cornea Service at Wills Eye Hospital. Only patients who had surgical repair of an open wound dehiscence were included, excluding those with wound slippage but no aqueous leak. RESULTS: The mean age at wound dehiscence was 56 years with a mean time from PK to dehiscence of 9.8 years. Among the 31 eyes, 26 (26/31, 84%) had trauma-induced dehiscence, while 5 had unknown causations or no reported trauma. The mean size of dehiscence was 153 ± 66 degrees. Visual outcomes ranged from 20/50 to no light perception, with a majority between 20/100 and hand motion (18/30, 60%). Twenty eyes (20/26, 76%) lost their lens at dehiscence. All 10 phakic eyes lost their lenses. Five patients retained their lens implants and had a better mean visual outcome (average = 20/400) than the 10 patients who lost their implants (average = 20/800) (1 lens status was unknown postdehiscence). CONCLUSIONS: Wound dehiscence is a lifelong risk after PK regardless of the age, indication for corneal transplant, and time since transplant. A better visual outcome was associated with retained pseudophakia and clear corneas.

Indications and outcomes of corneal transplantation in geriatric patients.

PURPOSE: To identify the most common corneal transplant procedures, indications, coexisting ocular diseases, and outcomes in elderly patients, and to compare younger geriatric patients with super-geriatric patients. DESIGN: Retrospective case series. METHODS: Data of all patients 65 years old and older who underwent corneal transplantation at Wills Eye Institute from April 2007 to January 2013, and were followed up for at least 1 year, were collected. Two hundred seventy-one eyes of 253 patients were divided into 2 groups according to the age of the patient. RESULTS: Group I (65-79 years old) included 181 eyes and Group II (80 years and older) included 90 eyes. The most common indication was Fuchs endothelial dystrophy, with 78 eyes (43%) in Group I and 34 eyes (38%) in Group II. In Group I, 93 Descemet stripping endothelial keratoplasty (DSEK) (51%), 84 penetrating keratoplasty (PK) (46%), and 4 keratoprosthesis procedures(2%) were performed; in Group II, 37 DSEK (41%), 51 PK (57%), and 2 keratoprosthesis procedures (2%) were performed. Graft survival rate at last visit was 90% for Group I and 88% for Group II. Rejection occurred in 18 Group I eyes (10%) and 7 Group II eyes (8%) (P = .562). CONCLUSION: Endothelial abnormalities were more common indications and keratoconus was a less common indication for surgery in the elderly. Fuchs dystrophy was the leading indication for surgery in both super-geriatric and younger geriatric patients. Graft survival rate was slightly higher in the younger geriatric age group but was not statistically significant. In the elderly, there is an increased prevalence of both glaucoma and retinal diseases that can affect the visual outcomes after corneal transplantation.

Imaging of homeostatic, neoplastic, and injured tissues by HA-based probes.

An increase in hyaluronan (HA) synthesis, cellular uptake, and metabolism occurs during the remodeling of tissue microenvironments following injury and during disease processes such as cancer. We hypothesized that multimodality HA-based probes selectively target and detectably accumulate at sites of high HA metabolism, thus providing a flexible imaging strategy for monitoring disease and repair processes. Kinetic analyses confirmed favorable available serum levels of the probe following intravenous (i.v.) or subcutaneous (s.c.) injection. Nuclear (technetium-HA, (99m)Tc-HA, and iodine-HA, (125)I-HA), optical (fluorescent Texas Red-HA, TR-HA), and magnetic resonance (gadolinium-HA, Gd-HA) probes imaged liver ((99m)Tc-HA), breast cancer cells/xenografts (TR-HA, Gd-HA), and vascular injury ((125)I-HA, TR-HA). Targeting of HA probes to these sites appeared to result from selective HA receptor-dependent localization. Our results suggest that HA-based probes, which do not require polysaccharide backbone modification to achieve favorable half-life and distribution, can detect elevated HA metabolism in homeostatic, injured, and diseased tissues.

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB.

The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation, and survival, in large part by activating the protein kinase Akt/PKB. We show that inositol polyphosphate multikinase (IPMK) physiologically generates PIP(3) as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP(3) generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.

Promoción de la salud: su desarrollo se inicia con un cambio trascendental del concepto de salud / Promotion of the health: its development begins with a transcendental change of the health concept

La promoción de la salud no se opone al mejoramiento de los servicios de salud para la atención de riesgos y enfermedades, pero señala la necesidad de reorientarlos para que cumplan un mejor papel en el mejoreamiento de la salud colectiva. La participación comunitaria y el empoderamiento individual y colectivo, son elementos indispensables en toda agenda de acción de la Promoción de la Salud. Todos los países deben crear el entorno político, jurídico, educativo, social y económico apropiado, para apoyar la promoción de la salud. El enfoque biomédico por sí solo es insuficiente para lograr las metas de una mejor salud para todos los pueblos, al no considerar los condicionantes básicos de la salud, ni al ser humano en su totalidad. Los estilos de vida deben ser abordados con precaución de modo de no traspasar toda la responsabilidad por su salud a las personas, eludiendo así la responsabilidad y política.

Propuesta de un plan de promoción de la salud a través de estilos de vida saludable para adolescentes / Proposal of a plan promotion of the health through styles of healthful life adolescents

Las enfermedades crónicas no transmisibles son un problema de salud cada vez más prevalente en el mundo. La atención biologista de estos problemas sólo ha llevado a elevación descontrolada de los costos por internamientos, medicamentos y tecnología cara. Por ello se deben promover conductas humanas saludables desde la infancia y adolescencia, fortaleciendo aspectos de alimentación, actividad física, prevención de fumado; no solamente mediante el conocimiento de su beneficio al organismo, si no a través de una verdadera modificación de actitudes y prácticas de carácter permanente. Se elabora una propuesta de un plan de promoción de la salud para fomentar estilos de vida saludables orientado a los adolescentes.

Síndrome neuroanémico con polineuropatía mixta secundario a deficiencia de vitamina B 12: reporte de un caso / Neuroanemic syndrome with secundary mixed polyneuropathy a deficit in vitamin B 12: report of a case

Se reporta el caso de una paciente femenina de 40 años, portadora de hipertensión arterial y depresión en tratamiento, que presentó un cuadro de neuropatía periférica mixta, glositis, gastritis crónica atrófica, anemia macrocítica e hipotiroidismo primario asociado a un déficit de vitamina B 12, como parte de una anemia perniciosa.