Aurkin-A, a TPX2-aurora a small molecule inhibitor disrupts Alisertib-induced polyploidy in aggressive diffuse large B cell lymphoma.

Chemotherapy induced polyploidy is a mechanism of inherited drug resistance resulting in an aggressive disease course in cancer patients. Alisertib, an Aurora Kinase A (AK-A) ATP site inhibitor, induces cell cycle disruption resulting in polyaneuploidy in Diffuse Large B Cell Lymphoma (DLBCL). Propidium iodide flow cytometry was utilized to quantify alisertib induced polyploidy in U2932 and VAL cell lines. In U2932 cells, 1µM alisertib generated 8n+ polyploidy in 48% of the total cell population after 5 days of treatment. Combination of Aurkin A an AK-A/TPX2 site inhibitor, plus alisertib disrupted alisertib induced polyploidy in a dose-dependent manner with associated increased apoptosis. We generated a stable FUCCI U2932 cell line expressing Geminin-clover (S/G2/M) and cdt1-mKO (G1), to monitor cell cycle progression. Using this system, we identified alisertib induces polyploidy through endomitosis, which was eliminated with Aurkin A treatment. In a VAL mouse xenograft model, we show polyploidy generation in alisertib treated mice versus vehicle control or Aurkin A. Aurkin A plus alisertib significantly reduced polyploidy to vehicle control levels. Our in vitro and in vivo studies show that Aurkin A synergizes with alisertib and significantly decreases the alisertib dose needed to disrupt polyploidy while increasing apoptosis in DLBCL cells.

Polyploidy in Cancer: Causal Mechanisms, Cancer-Specific Consequences, and Emerging Treatments.

Drug resistance is the major determinant for metastatic disease and fatalities, across all cancers. Depending on the tissue of origin and the therapeutic course, a variety of biological mechanisms can support and sustain drug resistance. Although genetic mutations and gene silencing through epigenetic mechanisms are major culprits in targeted therapy, drug efflux and polyploidization are more global mechanisms that prevail in a broad range of pathologies, in response to a variety of treatments. There is an unmet need to identify patients at risk for polyploidy, understand the mechanisms underlying polyploidization, and to develop strategies to predict, limit, and reverse polyploidy thus enhancing efficacy of standard-of-care therapy that improve better outcomes. This literature review provides an overview of polyploidy in cancer and offers perspective on patient monitoring and actionable therapy.

Using cfDNA and ctDNA as Oncologic Markers: A Path to Clinical Validation.

The detection of circulating tumor DNA (ctDNA) in liquid biopsy samples as an oncological marker is being used in clinical trials at every step of clinical management. As ctDNA-based liquid biopsy kits are developed and used in clinics, companies work towards increased convenience, accuracy, and cost over solid biopsies and other oncological markers. The technology used to differentiate ctDNA and cell-free DNA (cfDNA) continues to improve with new tests and methodologies being able to detect down to mutant allele frequencies of 0.001% or 1/100,000 copies. Recognizing this development in technology, the FDA has recently given pre-market approval and breakthrough device designations to multiple companies. The purpose of this review is to look at the utility of measuring total cfDNA, techniques used to differentiate ctDNA from cfDNA, and the utility of different ctDNA-based liquid biopsy kits using relevant articles from PubMed, clinicaltrials.gov, FDA approvals, and company newsletters. Measuring total cfDNA could be a cost-effective, viable prognostic marker, but various factors do not favor it as a monitoring tool during chemotherapy. While there may be a place in the clinic for measuring total cfDNA in the future, the lack of standardization means that it is difficult to move forward with large-scale clinical validation studies currently. While the detection of ctDNA has promising standardized liquid biopsy kits from various companies with large clinical trials ongoing, their applications in screening and minimal residual disease can suffer from lower sensitivity. However, researchers are working towards solutions to these issues with innovations in technology, multi-omics, and sampling. With great promise, further research is needed before liquid biopsies can be recommended for everyday clinical management.

The Role of Therapeutic Anticoagulation in COVID-19.

Coagulopathy has proven to be a common complication of the novel coronavirus SARS-CoV-2, with evidence of elevated D-dimers and fibrin degradation products associated with an increased incidence of thromboembolism. Despite emerging evidence describing the coagulopathy and its clinical relevance in COVID-19, fewer studies have addressed the potential role of empiric therapeutic anticoagulation in this setting. We report the case of a patient admitted to our intensive care unit (ICU) with severe acute respiratory distress syndrome (ARDS) secondary to COVID-19 whose clinical trajectory improved dramatically after initiation of a therapeutic dose of LMWH. The patient showed progressive elevation of fibrinogen and D-dimers despite a prophylactic dose of LMWH during her ICU stay. This was met with a moderate increase of troponin T-hs, an escalating need for vasopressors, and a progressive decrease in her P/F ratio despite preserved lung static compliance. Her platelet count was normal and had an elevated fibrinogen during the first week of ICU stay. The ECG was normal, and a bedside transthoracic echocardiogram showed no evidence of pulmonary embolism and a preserved EF with no regional wall motion abnormalities (RMWA). The chest X-ray was not dissimilar to previous exams, and the ABG showed hypoxia with normal pCO2 values. The decision was made to commence empiric therapeutic enoxaparin. The patient did not experience bleeding complications, and her clinical trajectory appeared to change dramatically. She was successfully extubated three days later and proceeded to clinical recovery and eventual discharge from the ICU. The available evidence shows that there is undoubtedly coagulopathy associated with COVID-19 with various subsequent forms of clinical manifestation described in the literature. Evidence also shows the benefits of heparin as an anticoagulant. From the discussion of this case report, however, it can be concluded that despite the plausible theoretical rationale, studies pertaining to the role of empiric therapeutic anticoagulation in this setting fall short of providing compelling evidence. Subsequently the role of empiric therapeutic anticoagulation in COVID-19 remains unclear with a pressing call for further research.

Macromolecular modeling and design in Rosetta: recent methods and frameworks.

The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.

Transforming Medicare's Payment Systems: Progress Shaped By The ACA.

The Affordable Care Act promoted payment reforms directly and through the creation of the Center for Medicare and Medicaid Innovation, which it endowed with the authority to introduce Alternative Payment Models (APMs) into Medicare and Medicaid. We conducted a narrative review of these payment reforms, finding that several programs generated modest savings while maintaining or improving the quality of care, but they had high dropout rates. In general, evidence for other APMs is less conclusive, and whether the reforms spurred similar changes in the private sector remains anecdotal. Despite challenges, APMs provide incentives for efficient care provision and offer providers a way to succeed financially in an environment with slowly rising fee-for-service prices. Thus, we consider the Affordable Care Act's payment reforms to be modestly successful, and we encourage both the purging of initiatives that aren't working and the continued development and study of promising ones.

Successive blood meals enhance virus dissemination within mosquitoes and increase transmission potential.

The recent Zika virus (ZIKV) and chikungunya virus epidemics highlight the explosive nature of arthropod-borne viruses (arboviruses) transmitted by Aedes spp. mosquitoes1,2. Vector competence and the extrinsic incubation period (EIP) are two key entomological parameters used to assess the public health risk posed by arboviruses3. These are typically measured empirically by offering mosquitoes an infectious blood meal and temporally sampling mosquitoes to determine the infection and transmission status. This approach has been used for the better part of a century; however, it does not accurately capture the biology and behaviour of many mosquito vectors that refeed frequently (every 2-3 d)4. Here, we demonstrate that acquisition of a second non-infectious blood meal significantly shortens the EIP of ZIKV-infected Aedes aegypti by enhancing virus dissemination from the mosquito midgut. Similarly, a second blood meal increases the competence of this species for dengue virus and chikungunya virus as well as Aedes albopictus for ZIKV, suggesting that this phenomenon may be common among other virus-vector pairings and that A. albopictus might be a more important vector than once thought. Blood-meal-induced microperforations in the virus-impenetrable basal lamina that surrounds the midgut provide a mechanism for enhanced virus escape. Modelling of these findings reveals that a shortened EIP would result in a significant increase in the basic reproductive number, R0, estimated from experimental data. This helps to explain how A. aegypti can sustain explosive epidemics such as ZIKV despite relatively poor vector competence in single-feed laboratory trials. Together, these data demonstrate a direct and unrecognized link between mosquito feeding behaviour, EIP and vector competence.

Hypothetical Network Adequacy Schemes For Children Fail To Ensure Patients' Access To In-Network Children's Hospital.

Insurers are increasingly adopting narrow network strategies. Little is known about how these strategies may affect children's access to needed specialty care. We examined the percentage of pediatric specialty hospitalizations that would be beyond existing Medicare Advantage network adequacy distance requirements for adult hospital care and, as a secondary analysis, a pediatric adaptation of the Medicare Advantage requirements. We examined 748,920 hospitalizations at eighty-one children's hospitals that submitted data for the period October 2014-September 2015. Nearly half of specialty hospitalizations were outside the Medicare Advantage distance requirements. Under the pediatric adaptation, there was great variability among the hospitals, with the percent of hospitalizations beyond the distance requirements ranging from less than 1 percent to 35 percent. Instead of, or in addition to, time and distance standards, policy makers may need to consider more nuanced network definitions, including functional capabilities of the pediatric care network or clear exception policies for essential specialty care services.

Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database.

Purpose Data that guide selection of optimal local ablative therapy for the management localized hepatocellular carcinoma (HCC) are lacking. Because there are limited prospective comparative data for these treatment modalities, we aimed to compare the effectiveness of radiofrequency ablation (RFA) versus stereotactic body radiotherapy (SBRT) by using the National Cancer Database. Methods We conducted an observational study to compare the effectiveness of RFA versus SBRT in nonsurgically managed patients with stage I or II HCC. Overall survival was compared by using propensity score-weighted and propensity score-matched analyses based on patient-, facility-, and tumor-level characteristics. A sensitivity analysis was performed to evaluate the effect of severe fibrosis/cirrhosis. In addition, we performed exploratory analyses to determine the effectiveness of RFA and SBRT in clinically relevant patient subsets. Results Overall, 3,684 (92.6%) and 296 (7.4%) nonsurgically managed patients with stage I or II HCC received RFA or SBRT, respectively. After propensity matching, 5-year overall survival was 29.8% (95% CI, 24.5% to 35.3%) in the RFA group versus 19.3% (95% CI, 13.5% to 25.9%) in the SBRT group ( P < .001). Inverse probability-weighted analysis yielded similar results. The benefit of RFA was consistent across all subgroups examined and was robust to the effects of severe fibrosis/cirrhosis. Conclusion Our study suggests that treatment with RFA yields superior survival compared with SBRT for nonsurgically managed patients with stage I or II HCC. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending local ablative therapy for localized unresectable HCC.

The Oncology Care Model: Perspectives From the Centers for Medicare & Medicaid Services and Participating Oncology Practices in Academia and the Community.

Cancer care delivery in the United States is often fragmented and inefficient, imposing substantial burdens on patients. Costs of cancer care are rising more rapidly than other specialties, with substantial regional differences in quality and cost. The Centers for Medicare & Medicaid Services (CMS) Innovation Center (CMMIS) recently launched the Oncology Care Model (OCM), which uses payment incentives and practice redesign requirements toward the goal of improving quality while controlling costs. As of March 2017, 190 practices were participating, with approximately 3,200 oncologists providing care for approximately 150,000 unique beneficiaries per year (approximately 20% of the Medicare Fee-for-Service population receiving chemotherapy for cancer). This article provides an overview of the program from the CMS perspective, as well as perspectives from two practices implementing OCM: an academic health system (Yale Cancer Center) and a community practice (Hematology Oncology Associates of Central New York). Requirements of OCM, as well as implementation successes, challenges, financial implications, impact on quality, and future visions, are provided from each perspective.

Design Challenges of an Episode-Based Payment Model in Oncology: The Centers for Medicare & Medicaid Services Oncology Care Model.

The Centers for Medicare & Medicaid Services developed the Oncology Care Model as an episode-based payment model to encourage participating practitioners to provide higher-quality, better-coordinated care at a lower cost to the nearly three-quarter million fee-for-service Medicare beneficiaries with cancer who receive chemotherapy each year. Episode payment models can be complex. They combine into a single benchmark price all payments for services during an episode of illness, many of which may be delivered at different times by different providers in different locations. Policy and technical decisions include the definition of the episode, including its initiation, duration, and included services; the identification of beneficiaries included in the model; and beneficiary attribution to practitioners with overall responsibility for managing their care. In addition, the calculation and risk adjustment of benchmark episode prices for the bundle of services must reflect geographic cost variations and diverse patient populations, including varying disease subtypes, medical comorbidities, changes in standards of care over time, the adoption of expensive new drugs (especially in oncology), as well as diverse practice patterns. Other steps include timely monitoring and intervention as needed to avoid shifting the attribution of beneficiaries on the basis of their expected episode expenditures as well as to ensure the provision of necessary medical services and the development of a meaningful link to quality measurement and improvement through the episode-based payment methodology. The complex and diverse nature of oncology business relationships and the specific rules and requirements of Medicare payment systems for different types of providers intensify these issues. The Centers for Medicare & Medicaid Services believes that by sharing its approach to addressing these decisions and challenges, it may facilitate greater understanding of the model within the oncology community and provide insight to others considering the development of episode-based payment models in the commercial or government sectors.