Systematic Identification of Druggable Epithelial-Stromal Crosstalk Signaling Networks in Ovarian Cancer.

BACKGROUND: Bulk tumor tissue samples are used for generating gene expression profiles in most research studies, making it difficult to decipher the stroma-cancer crosstalk networks. In the present study, we describe the use of microdissected transcriptome profiles for the identification of cancer-stroma crosstalk networks with prognostic value, which presents a unique opportunity for developing new treatment strategies for ovarian cancer. METHODS: Transcriptome profiles from microdissected ovarian cancer-associated fibroblasts (CAFs) and ovarian cancer cells from patients with high-grade serous ovarian cancer (n = 70) were used as input data for the computational systems biology program CCCExplorer to uncover crosstalk networks between various cell types within the tumor microenvironment. The crosstalk analysis results were subsequently used for discovery of new indications for old drugs in ovarian cancer by computational ranking of candidate agents. Survival analysis was performed on ovarian tumor-bearing Dicer/Pten double-knockout mice treated with calcitriol, a US Food and Drug Administration-approved agent that suppresses the Smad signaling cascade, or vehicle control (9-11 mice per group). All statistical tests were two-sided. RESULTS: Activation of TGF-ß-dependent and TGF-ß-independent Smad signaling was identified in a particular subtype of CAFs and was associated with poor patient survival (patients with higher levels of Smad-regulated gene expression by CAFs: median overall survival = 15 months, 95% confidence interval [CI] = 12.7 to 17.3 months; vs patients with lower levels of Smad-regulated gene expression: median overall survival = 26 months, 95% CI = 15.9 to 36.1 months, P = .02). In addition, the activated Smad signaling identified in CAFs was found to be targeted by repositioning calcitriol. Calcitriol suppressed Smad signaling in CAFs, inhibited tumor progression in mice, and prolonged the median survival duration of ovarian cancer-bearing mice from 36 to 48 weeks (P = .04). CONCLUSIONS: Our findings suggest the feasibility of using novel multicellular systems biology modeling to identify and repurpose known drugs targeting cancer-stroma crosstalk networks, potentially leading to faster and more effective cures for cancers.

Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance.

The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF-endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.

Formation of a zwitterionic boronium species from the reaction of a stable carbenoid with borane: CO2 reduction.

The treatment of Li2C(PPh2NMes)2 (1, Mes = 2,4,6-Me3C6H2) with hexachloroethane yielded the corresponding carbenoid 2 in good yields. The reactivity of 2 was studied with BH3·SMe2 to give a zwitterionic boronium species 4, also a stable carbenoid. Both carbenoid species were found to be excellent catalysts for the CO2 reduction by BH3·SMe2.

The dorsal metatarsal artery perforator flap.

Few options exist for the resurfacing of web-space and small soft tissue defects of the dorsum of the distal foot. The study examines the anatomy of the second to fourth dorsal metatarsal arteries in 16 fresh frozen cadavers to determine if the anatomy correlates to that in the hand, permitting the design of local flaps based on perforators of these vessels. A clinical case is also presented, illustrating the efficacy of such a perforator-based flap.Sixteen Asian cadaveric lower limbs were used for this study. The specimens were prepared with latex dye injection. Dissection under loupe magnification was carried out to determine the position and caliber of the cutaneous perforators from the dorsal metatarsal arteries, and the spread of the latex dye in the skin from these cutaneous perforators. One clinical case illustration of this perforator-based flap for distal foot defect resurfacing is presented.In our cadaveric study, each second to fourth dorsal metatarsal artery had between 2 and 5 cutaneous perforators with calibers of 0.5 to 0.7 mm in diameter. The most distal cutaneous perforator was present consistently, always arising between the heads of the respective metatarsals.In conclusion, the vascular anatomy of the second to fourth dorsal metatarsal arteries is similar to that in the hand, thus allowing for the design of reliable perforator-based flaps for distal foot resurfacing.

A chimaeric-pattern flap design for implantable Doppler surrogate monitoring: a novel placement technique.

INTRODUCTION AND AIM: Postoperative flap monitoring is a vital aspect of free tissue transfer in order to detect early vascular compromise and to enable early flap salvage. The implantable Doppler monitoring system is one of many monitoring devices used to ensure accuracy and reduce unnecessary flap explorations. However, there are a number of concerns with its use, namely tension on the anastomosis, possible vessel constriction and false-negative detection. This study aimed to alleviate these concerns, by introducing a new method of placing the implantable Doppler probe on the adjacent vessel limb of a chimaeric flap. This is illustrated by a case series of chimaeric free tissue flaps that allow this surrogate placement of the Doppler probe. METHODS: The flap is raised in a chimaeric fashion, with a main perforator pedicle to the skin or muscle paddle for the main reconstructive purpose and a side branch from the main pedicle going to a smaller adipofascial or muscle flap for monitoring. This branch vascular pedicle leading to the chimaeric tissue is kept sufficiently long to enable placement of the Doppler cuff and prevent turbulence. The probe of a Cook-Swartz implantable Doppler system is placed around the branch pedicle, approximately 5 mm from the branching point, and secured with a vessel clip. This is then secured away from the major vessels of the main free flap. Removal of the probe's crystal and wire is easily done with a single gentle traction on postoperative day 7. RESULTS: Five cases of chimaeric free flaps were performed with this manoeuvre: three thoracodorsal perforator chimaeric flaps for head-and-neck or extremity reconstruction, one latissimus dorsi neuromuscular chimaeric flap for facial reanimation and one digastric lymph node transfer for the treatment of lower limb lymphoedema. The Doppler system showed a low but sustained oscillating flow in all cases indicating vascular patency, with minimal flow interference from other large-calibre vessels. There was no discernible kinking on the anastomosis. There were no complications encountered during probe removal. This postoperative monitoring manoeuvre was done successfully with good results. CONCLUSION: The monitoring equipment is very sensitive to any flow disturbance due to positional changes in the head-and-neck region or the extremities and is able to detect flow changes in buried flaps postoperatively. Chimaeric flap composition is easier now than before because of perforator-oriented pedicle dissection, and surrogate Doppler monitoring is one more application of the chimaeric flap. This novel chimaeric fashion of implantable Doppler probe placement is a good surrogate measure of flow in the main pedicle.

Facile B-H bond activation of borane by stable carbenoid species.

Stable nucleophilic carbene compounds have recently been shown to be able to mimic in some instances the reactivity of metal fragments in the reaction of unactivated E-H bonds (E = H, R3Si, NH2, R2P). However, the insertion into a B-H bond of the strongly Lewis acidic BH3 molecule has never been observed at a single C atom or even at a metal fragment. Our results show that designed stable, highly electrophilic carbenoid fragments in compounds 4 and 6 can achieve this reactivity in a controlled manner. Density functional theory calculations corroborated the experimental results on the presently designed systems as well as the lack of reactivity on nucleophilic carbenes.

Blindness resulting from orbital cellulitis following rhinoplasty.

Ophthalmic complications occurring after non-ophthalmic surgery are rare. We present a case of orbital cellulitis in a 24-year-old woman, who had undergone augmentation rhinoplasty in combination with breast augmentation. Symptoms included pain, swelling, erythema and eventual loss of vision in the left eye. Intravenous administration of antibiotics did not halt the rapid progression of this infection. On the sixth postoperative day, the patient underwent left-orbital evisceration to prevent the spread of infection to other organ systems. Despite aggressive therapy, the sequela was permanent, unilateral blindness. Orbital cellulitis in aesthetic surgery is extremely rare. In patients undergoing rhinoplasties that may be prolonged due to other concomitant cosmetic procedures, aseptic preoperative preparation and careful monitoring for signs of orbital infection are recommended.

Accelerated osteomesh resorption: a case report.

Facial fractures occur commonly as a result of blunt trauma from road traffic accidents, assaults, and sporting injuries. Orbital floor fractures form a significant proportion of these and when large enough, the defect often requires surgical reconstruction of the floor to prevent orbital content herniation. Here, we present a case of a 28-year-old gentleman, who sustained an orbital floor fracture from a soccer-related injury. The resulting floor defect was surgically repaired using an osteomesh that was hand-cut to size. He developed delayed enophthalmos and entrapment of the inferior rectus muscle due to early resorption of the osteomesh, requiring revision surgery.