Tumor Immune Microenvironment in Gynecologic Cancers.

Gynecologic cancers have varying response rates to immunotherapy due to the heterogeneity of each cancer's molecular biology and features of the tumor immune microenvironment (TIME). This article reviews key features of the TIME and its role in the pathophysiology and treatment of ovarian, endometrial, cervical, vulvar, and vaginal cancer. Knowledge of the role of the TIME in gynecologic cancers has been rapidly developing with a large body of preclinical studies demonstrating an intricate yet dichotomous role that the immune system plays in either supporting the growth of cancer or opposing it and facilitating effective treatment.

Integrating Precision Medicine into the Contemporary Management of Gynecologic Cancers.

Purpose Of Review: The treatment of patients with advanced gynecologic malignancies remains challenging. Advancements in genomics have led to recognition and development of individualized therapeutic targets. This article reviews the current trends in precision medicine for treatment of gynecologic cancers.

The current status of secondary cytoreduction in ovarian cancer: a systematic review.

Purpose: Ovarian cancer causes more deaths than any other cancer of the female genital tract. Despite improvements in management and treatment, survival remains low in patients with extensive disease at presentation, which usually leads to eventual recurrence. Treatment of recurrence remains challenging.

Association between Cervical Dysplasia and Adverse Pregnancy Outcomes.

Objective: The aim of this study was to determine if cervical dysplasia during pregnancy is associated with pregnancy complications, including preterm delivery and pre-eclampsia.

Study Design: A retrospective cohort analyses was performed with propensity-score matching to compare complication rates between pregnant women without history of abnormal cervical cancer screening and pregnant women referred for cervical dysplasia assessment to colposcopy clinic. A composite outcome of pregnancy complications included intra-amniotic infection, preterm premature rupture of membranes, pre-eclampsia, preterm delivery, low birth weight, oligohydramnios, and intrauterine fetal demise.

Survival after Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer.

Background: Minimally invasive surgery was adopted as an alternative to laparotomy (open surgery) for radical hysterectomy in patients with early-stage cervical cancer before high-quality evidence regarding its effect on survival was available. We sought to determine the effect of minimally invasive surgery on all-cause mortality among women undergoing radical hysterectomy for cervical cancer.

Methods: We performed a cohort study involving women who underwent radical hysterectomy for stage IA2 or IB1 cervical cancer during the 2010-2013 period at Commission on Cancer-accredited hospitals in the United States.

Combinatorial lentiviral gene delivery of pro-oligodendrogenic factors for improving myelination of regenerating axons after spinal cord injury.

Spinal cord injury (SCI) results in paralysis below the injury and strategies are being developed that support axonal regrowth, yet recovery lags, in part, because many axons are not remyelinated. Herein, we investigated strategies to increase myelination of regenerating axons by overexpression of platelet-derived growth factor (PDGF)-AA and noggin either alone or in combination in a mouse SCI model. Noggin and PDGF-AA have been identified as factors that enhance recruitment and differentiation of endogenous progenitors to promote myelination.

Endpoint-restricted adiabatic free energy dynamics approach for the exploration of biomolecular conformational equilibria.

A method for calculating the free energy difference between two structurally defined conformational states of a chemical system is developed. A path is defined using a previously reported collective variable that interpolates between two or more conformations, and a restraint is introduced in order to keep the system close to the path. The evolution of the system along the path, which typically presents a high free energy barrier, is generated using enhanced sampling schemes.

Local Immunomodulation with Anti-inflammatory Cytokine-Encoding Lentivirus Enhances Functional Recovery after Spinal Cord Injury.

Trauma to the spinal cord and associated secondary inflammation can lead to permanent loss of sensory and motor function below the injury level, with the resulting environment serving as a barrier that limits regeneration. In this study, we investigate the localized expression of anti-inflammatory cytokines IL-10 and IL-4 via lentiviral transduction in multichannel bridges. Porous multichannel bridges provide physical guidance for axonal outgrowth with the cytokines hypothesized to modulate the neuroinflammatory microenvironment and enhance axonal regeneration.

Reducing neuroinflammation by delivery of IL-10 encoding lentivirus from multiple-channel bridges.

The spinal cord is unable to regenerate after injury largely due to growth-inhibition by an inflammatory response to the injury that fails to resolve, resulting in secondary damage and cell death. An approach that prevents inhibition by attenuating the inflammatory response and promoting its resolution through the transition of macrophages to anti-inflammatory phenotypes is essential for the creation of a growth permissive microenvironment. Viral gene delivery to induce the expression of anti-inflammatory factors provides the potential to provide localized delivery to alter the host inflammatory response.

Tissue Engineering Approaches to Modulate the Inflammatory Milieu following Spinal Cord Injury.

Tissue engineering strategies have shown promise in promoting healing and regeneration after spinal cord injury (SCI); however, these strategies are limited by inflammation and the immune response. Infiltration of cells of the innate and adaptive immune responses and the inflammation that follows cause secondary damage adjacent to the injury, increased scarring, and a potently inhibitory environment for the regeneration of damaged neurons. While the inflammation that ensues is typically associated with limited regeneration, the immune response is a crucial element in the closing of the blood-brain barrier, minimizing the spread of injury, and initiating healing.

Advanced Potential Energy Surfaces for Molecular Simulation.

Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC) architectures, such as multicore CPUs and modern graphics processing units (GPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware platforms.

A Stochastic, Resonance-Free Multiple Time-Step Algorithm for Polarizable Models That Permits Very Large Time Steps.

Molecular dynamics remains one of the most widely used computational tools in the theoretical molecular sciences to sample an equilibrium ensemble distribution and/or to study the dynamical properties of a system. The efficiency of a molecular dynamics calculation is limited by the size of the time step that can be employed, which is dictated by the highest frequencies in the system. However, many properties of interest are connected to low-frequency, long time-scale phenomena, requiring many small time steps to capture.

Semi-automated counting of axon regeneration in poly(lactide co-glycolide) spinal cord bridges.

Background: Spinal cord injury (SCI) is a debilitating event with multiple mechanisms of degeneration leading to life-long paralysis. Biomaterial strategies, including bridges that span the injury and provide a pathway to reconnect severed regions of the spinal cord, can promote partial restoration of motor function following SCI. Axon growth through the bridge is essential to characterizing regeneration, as recovery can occur via other mechanisms such as plasticity.

Long-term characterization of axon regeneration and matrix changes using multiple channel bridges for spinal cord regeneration.

Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. The host response to SCI is typified by limited endogenous repair, and biomaterial bridges offer the potential to alter the microenvironment to promote regeneration. Porous multiple channel bridges implanted into the injury provide stability to limit secondary damage and support cell infiltration that limits cavity formation.

Multifunctional, multichannel bridges that deliver neurotrophin encoding lentivirus for regeneration following spinal cord injury.

Therapeutic strategies following spinal cord injury must address the multiple barriers that limit regeneration. Multiple channel bridges have been developed that stabilize the injury following implantation and provide physical guidance for regenerating axons. These bridges have now been employed as a vehicle for localized delivery of lentivirus.