Understanding the spectrum of malignant bowel obstructions in gynecologic cancers and the application of the Henry score.

OBJECTIVE: Malignancy-associated bowel obstruction (MBO) is a potential sequela of advanced gynecologic cancers, adversely impacting both quality of life and prognosis. The Henry score (HS) was developed in a gastrointestinal cancer-predominant population to predict 30-day mortality. We aim to characterize MBO in gynecologic cancers and assess the utility of the HS in this population. METHODS: This is a retrospective review of patients with gynecologic cancer and MBO admitted to a single academic institution from 2016 to 2021. The primary outcome is to characterize malignant small and large bowel obstructions in primary and recurrent gynecologic cancer using readmission and mortality rates. Secondary outcomes are to assess the Henry score and inpatient MBO management. RESULTS: 179 patients totaling 269 were admissions identified, most commonly affecting patients with ovarian cancer. The majority (89.4%) were managed non-operatively while 10.6% were managed surgically. No significant differences were observed in survival for medical versus surgical management. Thirty-day mortality increased with increasing HS (0%, 0-1; 14.3%, 2-3; 40.9%, 4-5). Over 1/3 (34.1%) of patients were readmitted for recurrent or persistent MBO. Goals of care conversations were documented for 56.8% of patients with HS 4-5. Mortality rates across the entire cohort were high-20.1% and 60.9% had died by 1 and 6 months, respectively. CONCLUSIONS: Survival rates following an initial MBO admission are poor. The HS has utility in gynecologic cancers for assessing 30-day mortality and may be a useful tool to aid in the management and counseling of patients with gynecologic cancer and MBO.

Rap1 regulates apical contractility to allow embryonic morphogenesis without tissue disruption and acts in part via Canoe-independent mechanisms.

Embryonic morphogenesis is powered by dramatic changes in cell shape and arrangement driven by the cytoskeleton and its connections to adherens junctions. This requires robust linkage allowing morphogenesis without disrupting tissue integrity. The small GTPase Rap1 is a key regulator of cell adhesion, controlling both cadherin-mediated and integrin-mediated processes. We have defined multiple roles in morphogenesis for one Rap1 effector, Canoe/Afadin, which ensures robust junction-cytoskeletal linkage. We now ask what mechanisms regulate Canoe and other junction-cytoskeletal linkers during Drosophila morphogenesis, defining roles for Rap1 and one of its guanine nucleotide exchange factor (GEF) regulators, Dizzy. Rap1 uses Canoe as one effector, regulating junctional planar polarity. However, Rap1 has additional roles in junctional protein localization and balanced apical constriction-in its absence, Bazooka/Par3 localization is fragmented, and cells next to mitotic cells apically constrict and invaginate, disrupting epidermal integrity. In contrast, the GEF Dizzy has phenotypes similar to but slightly less severe than Canoe loss, suggesting that this GEF regulates Rap1 action via Canoe. Taken together, these data reveal that Rap1 is a crucial regulator of morphogenesis, likely acting in parallel via Canoe and other effectors, and that different Rap1 GEFs regulate distinct functions of Rap1.

ALK1 regulates the internalization of endoglin and the type III TGF-ß receptor.

Complex formation and endocytosis of transforming growth factor-ß (TGF-ß) receptors play important roles in signaling. However, their interdependence remained unexplored. Here, we demonstrate that ALK1, a TGF-ß type I receptor prevalent in endothelial cells, forms stable complexes at the cell surface with endoglin and with type III TGF-ß receptors (TßRIII). We show that ALK1 undergoes clathrin-mediated endocytosis (CME) faster than ALK5, type II TGF-ß receptor (TßRII), endoglin, or TßRIII. These complexes regulate the endocytosis of the TGF-ß receptors, with a major effect mediated by ALK1. Thus, ALK1 enhances the endocytosis of TßRIII and endoglin, while ALK5 and TßRII mildly enhance endoglin, but not TßRIII, internalization. Conversely, the slowly endocytosed endoglin has no effect on the endocytosis of either ALK1, ALK5, or TßRII, while TßRIII has a differential effect, slowing the internalization of ALK5 and TßRII, but not ALK1. Such effects may be relevant to signaling, as BMP9-mediated Smad1/5/8 phosphorylation is inhibited by CME blockade in endothelial cells. We propose a model that links TGF-ß receptor oligomerization and endocytosis, based on which endocytosis signals are exposed/functional in specific receptor complexes. This has broad implications for signaling, implying that complex formation among various receptors regulates their surface levels and signaling intensities.

Endoglin interacts with VEGFR2 to promote angiogenesis.

Endoglin, a TGF-ß coreceptor predominantly expressed in endothelial cells, plays an important role in vascular development and tumor-associated angiogenesis. However, the mechanism by which endoglin regulates angiogenesis, especially during tip cell formation, remains largely unknown. In this study, we report that endoglin promoted VEGF-induced tip cell formation. Mechanistically, endoglin interacted with VEGF receptor (VEGFR)-2 in a VEGF-dependent manner, which sustained VEGFR2 on the cell surface and prevented its degradation. Endoglin mutants deficient in the ability to interact with VEGFR2 failed to sustain VEGFR2 on the cell surface and to promote VEGF-induced tip cell formation. Further, an endoglin-targeting monoclonal antibody (mAb), TRC105, cooperated with a VEGF-A targeting mAb, bevacizumab, to inhibit VEGF signaling and tip cell formation in vitro and to inhibit tumor growth, metastasis, and tumor-associated angiogenesis in a murine tumor model. This study demonstrate a novel mechanism by which endoglin initiates and regulates VEGF-driven angiogenesis while providing a rationale for combining anti-VEGF and anti-endoglin therapy in patients with cancer.-Tian, H., Huang, J. J., Golzio, C., Gao, X., Hector-Greene, M., Katsanis, N., Blobe, G. C. Endoglin interacts with VEGFR2 to promote angiogenesis.

Stabilization of T4 bacteriophage at acidic and basic pH by adsorption on paper.

Bacteriophages find applications in agriculture, medicine, and food safety. Many of these applications can expose bacteriophages to stresses that inactivate them including acidic and basic pH. Bacteriophages can be stabilized against these stresses by materials including paper, a common material in packaging and consumer products. Combining paper and bacteriophages creates antibacterial materials, which can reduce the use of antibiotics. Here we show that adsorption on paper protects T4, T5, and T7 bacteriophage from acidic and basic pH. We added bacteriophages to filter paper functionalized with carboxylic acid (carboxyl methyl cellulose) or amine (chitosan) groups, and exposed them to pH from 5.6 to 14. We determined the number of infective bacteriophages after exposure directly on the paper. All papers extended the lifetime of infective bacteriophage by at least a factor of four with some papers stabilizing bacteriophages for up to one week. The degree of stabilization depended on five main factors (i) the family of the bacteriophage, (ii) the charge of the paper and bacteriophages, (iii) the location of the bacteriophages within the paper, (iv) the ability of the paper to prevent bacteriophage-bacteriophage aggregation, and (v) the sensitivity of the bacteriophage proteins to the tested pH. Even when adsorbed on paper the bacteriophages were able to remove E. coli in milk. Choosing the right paper modification or material will protect bacteriophages adsorbed on that material against detrimental pH and other environmental challenges increasing the range of applications of bacteriophages on materials.

Low-Cost Sensor System Design for In-Home Physical Activity Tracking.

An aging and more sedentary population requires interventions aimed at monitoring physical activity, particularly within the home. This research uses simulation, optimization, and regression analyses to assess the feasibility of using a small number of sensors to track movement and infer physical activity levels of older adults. Based on activity data from the American Time Use Survey and assisted living apartment layouts, we determined that using three to four doorway sensors can be used to effectively capture a sufficient amount of movements in order to estimate activity. The research also identified preferred approaches for assigning sensor locations, evaluated the error magnitude inherent in the approach, and developed a methodology to identify which apartment layouts would be best suited for these technologies.

TßRIII independently binds type I and type II TGF-ß receptors to inhibit TGF-ß signaling.

Transforming growth factor-ß (TGF-ß) receptor oligomerization has important roles in signaling. Complex formation among type I and type II (TßRI and TßRII) TGF-ß receptors is well characterized and is essential for signal transduction. However, studies on their interactions with the type III TGF-ß coreceptor (TßRIII) in live cells and their effects on TGF-ß signaling are lacking. Here we investigated the homomeric and heteromeric interactions of TßRIII with TßRI and TßRII in live cells by combining IgG-mediated patching/immobilization of a given TGF-ß receptor with fluorescence recovery after photobleaching studies on the lateral diffusion of a coexpressed receptor. Our studies demonstrate that TßRIII homo-oligomerization is indirect and depends on its cytoplasmic domain interactions with scaffold proteins (mainly GIPC). We show that TßRII and TßRI bind independently to TßRIII, whereas TßRIII augments TßRI/TßRII association, suggesting that TßRI and TßRII bind to TßRIII simultaneously but not as a complex. TßRIII expression inhibited TGF-ß-mediated Smad2/3 signaling in MDA-MB-231 cell lines, an effect that depended on the TßRIII cytoplasmic domain and did not require TßRIII ectodomain shedding. We propose that independent binding of TßRI and TßRII to TßRIII competes with TßRI/TßRII signaling complex formation, thus inhibiting TGF-ß-mediated Smad signaling.

Regulation of TGF-ß receptor hetero-oligomerization and signaling by endoglin.

Complex formation among transforming growth factor-ß (TGF-ß) receptors and its modulation by coreceptors represent an important level of regulation for TGF-ß signaling. Oligomerization of ALK5 and the type II TGF-ß receptor (TßRII) has been thoroughly investigated, both in vitro and in intact cells. However, such studies, especially in live cells, are missing for the endothelial cell coreceptor endoglin and for the ALK1 type I receptor, which enables endothelial cells to respond to TGF-ß by activation of both Smad2/3 and Smad1/5/8. Here we combined immunoglobulin G-mediated immobilization of one cell-surface receptor with lateral mobility studies of a coexpressed receptor by fluorescence recovery after photobleaching (FRAP) to demonstrate that endoglin forms stable homodimers that function as a scaffold for binding TßRII, ALK5, and ALK1. ALK1 and ALK5 bind to endoglin with differential dependence on TßRII, which plays a major role in recruiting ALK5 to the complex. Signaling data indicate a role for the quaternary receptor complex in regulating the balance between TGF-ß signaling to Smad1/5/8 and to Smad2/3.

Type III TGF-ß receptor downregulation generates an immunotolerant tumor microenvironment.

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-ß receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-ß signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-ß signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-ß inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.

Trajectories of perceived adult and peer discrimination among Black, Latino, and Asian American adolescents: patterns and psychological correlates.

This article presents results from a 3-year longitudinal study of the growth patterns and correlates of perceived discrimination by adults and by peers among Black, Latino, and Asian American high school students. Results revealed a linear increase over time in levels of perceived discrimination by adults, whereas perceptions of discrimination by peers remained stable over time. Asian American and non-Puerto Rican Latino adolescents (primarily Dominican) reported higher levels of peer and/or adult discrimination than did Puerto Rican youth, whereas Black adolescents reported a steeper increase over time in levels of perceived discrimination by peers and by adults than did Puerto Rican adolescents. Peer and adult discrimination was significantly associated with decreased self-esteem and increased depressive symptoms over time. Ethnic identity and ethnicity were found to moderate the relationships between perceived discrimination and changes in psychological well-being over time. Results underscore the need to include perceptions of discrimination when studying the development and well-being of ethnic minority adolescents.