ASCO strives, through research, education, and promotion of the highest quality of patient care, to create a world where cancer is prevented and every survivor is healthy. In this pursuit, cancer health equity remains the guiding institutional principle that applies to all its activities across the cancer care continuum. In 2009, ASCO committed to addressing differences in cancer outcomes in its original policy statement on cancer disparities. Over the past decade, despite novel diagnostics and therapeutics, together with changes in the cancer care delivery system such as passage of the Affordable Care Act, cancer disparities persist. Our understanding of the populations experiencing disparate outcomes has likewise expanded to include the intersections of race/ethnicity, geography, sexual orientation and gender identity, sociodemographic factors, and others. This updated statement is intended to guide ASCO’s future activities and strategies to achieve its mission of conquering cancer for all populations. ASCO acknowledges that much work remains to be done, by all cancer stakeholders at the systems level, to overcome historical momentum and existing social structures responsible for disparate cancer outcomes. This updated statement affirms ASCO’s commitment to moving beyond descriptions of differences in cancer outcomes toward achievement of cancer health equity, with a focus on improving equitable access to care, improving clinical research, addressing structural barriers, and increasing awareness that results in measurable and timely action toward achieving cancer health equity for all.
All coronaviruses encode a macrodomain containing ADP-ribose-1؆-phosphatase (ADRP) activity within the N terminus of nonstructural protein 3 (nsp3). Previous work showed that mouse hepatitis virus strain A59 (MHV-A59) with a mutated catalytic site (N1348A) replicated similarly to wild-type virus but was unable to cause acute hepatitis in mice. To determine whether this attenuated phenotype is applicable to multiple disease models, we mutated the catalytic residue in the JHM strain of MHV (JHMV), which causes acute and chronic encephalomyelitis, using a newly developed bacterial artificial chromosome (BAC)-based MHV reverse genetics system. Infection of mice with the macrodomain catalytic point mutant virus (N1347A) resulted in reductions in lethality, weight loss, viral titers, proinflammatory cytokine and chemokine expression, and immune cell infiltration in the brain compared to mice infected with wild-type virus. Specifically, macrophages were most affected, with approximately 2.5-fold fewer macrophages at day 5 postinfection in N1347A-infected brains. Tumor necrosis factor (TNF) and interferon (IFN) signaling were not required for effective host control of mutant virus as all N1347A virus-infected mice survived the infection. However, the adaptive immune system was required for protection since N1347A virus was able to cause lethal encephalitis in RAG1؊/؊ (recombination activation gene 1 knockout) mice although disease onset was modestly delayed. Overall, these results indicate that the BAC-based MHV reverse genetics system will be useful for studies of JHMV and expand upon previous studies, showing that the macrodomain is critical for the ability of coronaviruses to evade the immune system and promote viral pathogenesis. IMPORTANCECoronaviruses are an important cause of human and veterinary diseases worldwide. Viral processes that are conserved across a family are likely to be good targets for the development of antiviral therapeutics and vaccines. The macrodomain is a ubiquitous structural domain and is also conserved among all coronaviruses. The coronavirus macrodomain has ADP-ribose-1؆-phosphatase activity; however, its function during infection remains unclear as does the reason that coronaviruses have maintained this enzymatic activity throughout evolution. For MHV, this domain has now been shown to promote multiple types of disease, including hepatitis and encephalitis. These data indicate that this domain is vital for the virus to replicate and cause disease. Understanding the mechanism used by this enzyme to promote viral pathogenesis will open up novel avenues for therapies and may give further insight into the role of macrodomain proteins in the host cell since these proteins are found in all living organisms.
Metastatic squamous cell carcinoma (SCCA) of the anal canal is a rare malignancy for which no standard treatment algorithm exists. To determine the best approach, all patients diagnosed with metastatic SCCA of the anal canal treated at a single institution were evaluated for choice of chemotherapy and treatment outcome. A retrospective study from January 2000 to May 2012 was conducted. Electronic medical records were reviewed for diagnosis of metastatic SCCA of the anal canal. All patients were treatment naïve for metastatic disease and completed all radiographic imaging at our institution. The purpose of this study was to evaluate outcomes among patients who received systemic chemotherapy and if appropriate were referred for multidisciplinary intervention (e.g., surgery, radiofrequency ablation, etc.). Seventy-seven patients fulfilled eligibility criteria. Forty-two patients (55%) received 5-fluorouracil (5-FU) + cisplatin (PF); 24 patients (31%) received carboplatin + paclitaxel (CP); 11 patients (14%) received an alternative regimen. After a median follow-up of 42 months, the median progression-free survival (PFS) for all patients was 7 months; the median overall survival (OS) was 22 months. Thirty-three patients (43%) underwent multidisciplinary management for metastatic disease resulting in a median PFS of 16 months (95% CI: 9·2 −22·8) and median OS of 53 months (95% CI: 28·3 – 77·6). Systemic chemotherapy provides durable survival for patients with surgically unresectable metastatic SCCA of the anal canal. Multidisciplinary management for select patients with metastatic disease effectively improves survival and should be considered whenever possible.
This report presents the American Society of Clinical Oncology’s (ASCO’s) evaluation of the adaptations in care delivery, research operations, and regulatory oversight made in response to the coronavirus pandemic and presents recommendations for moving forward as the pandemic recedes. ASCO organized its recommendations for clinical research around five goals to ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality. The specific goals are: (1) ensure that clinical research is accessible, affordable, and equitable; (2) design more pragmatic and efficient clinical trials; (3) minimize administrative and regulatory burdens on research sites; (4) recruit, retain, and support a well-trained clinical research workforce; and (5) promote appropriate oversight and review of clinical trial conduct and results. Similarly, ASCO also organized its recommendations regarding cancer care delivery around five goals: (1) promote and protect equitable access to high-quality cancer care; (2) support safe delivery of high-quality cancer care; (3) advance policies to ensure oncology providers have sufficient resources to provide high-quality patient care; (4) recognize and address threats to clinician, provider, and patient well-being; and (5) improve patient access to high-quality cancer care via telemedicine. ASCO will work at all levels to advance the recommendations made in this report.
Previous studies have demonstrated that the murine coronavirus mouse hepatitis virus (MHV) nonstructural protein 2 (ns2) is a 2=,5=-phosphodiesterase that inhibits activation of the interferon-induced oligoadenylate synthetase (OAS)-RNase L pathway. Enzymatically active ns2 is required for efficient MHV replication in macrophages, as well as for the induction of hepatitis in C57BL/6 mice. In contrast, following intranasal or intracranial inoculation, efficient replication of MHV in the brain is not dependent on an enzymatically active ns2. The replication of wild-type MHV strain A59 (A59) and a mutant with an inactive phosphodiesterase (ns2-H126R) was assessed in primary hepatocytes and primary central nervous system (CNS) cell types-neurons, astrocytes, and oligodendrocytes. A59 and ns2-H126R replicated with similar kinetics in all cell types tested, except macrophages and microglia. RNase L activity, as assessed by rRNA cleavage, was induced by ns2-H126R, but not by A59, and only in macrophages and microglia. Activation of RNase L correlated with the induction of type I interferon and the consequent high levels of OAS mRNA induced in these cell types. Pretreatment of nonmyeloid cells with interferon restricted A59 and ns2-H126R to the same extent and failed to activate RNase L following infection, despite induction of OAS expression. However, rRNA degradation was induced by treatment of astrocytes or oligodendrocytes with poly(I·C). Thus, RNase L activation during MHV infection is cell type specific and correlates with relatively high levels of expression of OAS genes, which are necessary but not sufficient for induction of an effective RNase L antiviral response.T he murine coronavirus mouse hepatitis virus (MHV) is an enveloped, positive-strand RNA virus of the coronavirus family within the nidovirus order. MHV is a collection of strains with tropisms for different organs, including the liver and central nervous system (CNS), and thus provides models for the study of acute encephalitis and hepatitis, as well as chronic demyelinating disease. The MHV-A59 strain (A59) used in this study induces mild encephalitis and moderate hepatitis. Studies of the pathogenesis of MHV strains and recombinant chimeric MHVs have shown that postentry virus-host interactions have significant impact on organ tropism and virulence in MHV-infected mice (1, 2).The type I interferon (IFN) response is an early innate response that is crucial to survival of mice following infection with many viruses, including MHV (3-5). During infection, viral doublestranded RNA (dsRNA) is recognized by pattern recognition receptors, such as MDA5 in the case of MHV in most cell types (3-5); this leads to the synthesis of type I IFN (Fig. 1). Alpha/beta IFN (IFN-␣/) induces expression of interferon-stimulated genes (ISGs) encoding pattern recognition receptors, transcription factors, and antiviral effectors, including multiple oligoadenylate synthetase (OAS) proteins. Viral dsRNA directly binds to and activates OAS to synthesize 2=,5=-linked oligoaden...
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