Project description:Poliovirus is the most extensively studied member of the order Picornavirales, which contains numerous medical, veterinary and agricultural pathogens. The picornavirus genome encodes a single polyprotein that is divided into three regions: P1, P2 and P3. P3 proteins are known to participate more directly in genome replication, for example by containing the viral RNA-dependent RNA polymerase (RdRp or 3Dpol), among several other proteins and enzymes. We will review recent data that provide new insight into the structure, function and mechanism of P3 proteins and their complexes, which are required for initiation of genome replication. Replication of poliovirus genomes occurs within macromolecular complexes, containing viral RNA, viral proteins and host-cell membranes, collectively referred to as replication complexes. P2 proteins clearly contribute to interactions with the host cell that are required for virus multiplication, including formation of replication complexes. We will discuss recent data that suggest a role for P3 proteins in formation of replication complexes. Among the least understood steps of the poliovirus lifecycle is encapsidation of genomic RNA. We will also describe data that suggest a role for P3 proteins in this step.
Project description:The mainstay of treatment for men with three or fewer non-castrate metastatic lesions outside of the prostate remains morbid palliative androgen deprivation therapy. We believe there is now a significant body of retrospective literature to suggest a survival benefit if these men have radical treatment to their primary tumour alongside 'metastasis-directed therapy' to the metastatic deposits. However, this regimen should be reserved to high-volume centres with quality assurance programmes and excellent outcomes. Patients should be made clear as to the uncertainty of benefit for this multi-site treatment strategy, and we await the publication of randomised controlled trials reporting in the next 5 years.
Project description:The concept of oligometastatic disease was first described by Hellman and Weichselbaum in 1995. The mere insight of this concept led to the hypothesis that this disease may be cured using local ablative weapons. Surgery has already demonstrated this hypothesis. Surgery limitations, either technical or due to refusal or associated comorbidity, have led to implement alternative ablative options such as stereotactic body radiation therapy (SBRT). SBRT evolved from (stereotactic radiosurgery) because of the need to irradiate extracranial lesions and has been shown to be safe and effective. SBRT achieves local control rates ranging from 70%-90%, but highly variable survival rates depending on the group analyzed. Series with heterogeneous metastatic sites and tumor origin have reported 20% survival rates at 2-3 years, similar to those achieved with surgery. Despite its excellent results, SBRT still faces significant clinical challenges. Its optimal integration with systemic treatment is unknown, and response assessment is very difficult. However, the greatest challenge lies in selection of patients most likely to remain oligometastatic, those who will most benefit from the technique. Biomarkers, molecular signatures, that accurately predict the biological behavior of malignancy are needed. The expression profile of specific miRNAs has been shown to have a potential in this regard.
Project description:Liver metastasis in solid tumors, including colorectal cancer, is the most frequent and lethal complication. The development of systemic therapy has led to prolonged survival. However, in selected patients with a finite number of discrete lesions in liver, defined as oligometastatic state, additional local therapies such as surgical resection, radiofrequency ablation, cryotherapy, and radiotherapy can lead to permanent local disease control and improve survival. Among these, an advance in radiation therapy made it possible to deliver high dose radiation to the tumor more accurately, without impairing the liver function. In recent years, the introduction of stereotactic ablative radiotherapy (SABR) has offered even more intensive tumor dose escalation in a few fractions with reduced dose to the adjacent normal liver. Many studies have shown that SABR for oligometastases is effective and safe, with local control rates widely ranging from 50% to 100% at one or two years. And actuarial survival at one and two years has been reported ranging from 72% to 94% and from 30% to 62%, respectively, without severe toxicities. In this paper, we described the definition and technical aspects of SABR, clinical outcomes including efficacy and toxicity, and related parameters after SABR in liver oligometastases from colorectal cancer.
Project description:Investigating people with bowel symptoms uses a test that detects traces of blood in the stools, the FIT test. There are many possible reasons for positive tests. A few people have cancer. However, most participants with symptoms don’t have any serious bowel disease but have benign problems such as piles or irritable bowel syndrome (IBS). It is very difficult to diagnose on symptoms alone, those participants who have serious bowel disease and those who do not.
After a positive test, people are invited for colonoscopy - a sort of articulated tube that is passed up the bowel. Most people invited for colonoscopy don’t have cancer. Only about 5% of those with positive FIT tests have cancer. About 25% have other bowel diseases, but most have nothing serious wrong at all. So they have the inconvenience and discomfort of colonoscopy but don’t get any benefit from it.
The investigators want to try adding another test, the volatile organic compound (VOC) test, to see if the investigators can separate those with positive FIT tests who do have something wrong, from those who don’t. The VOC test uses a urine sample. Using both tests might also be better for detecting cancer. FIT alone misses about 20%.
So the investigators think that using both tests might not only be better for detecting cancer, but also might mean that a lot of people will avoid having to have colonoscopy.
This study will recruit 1,819 participants with bowel symptoms from NHS trusts in the UK. They will provide stool samples for FIT and urine for VOC analysis. They will have colonoscopy to get a definite diagnosis. Then the investigators will look at their FIT and VOC test results to see if in future, people with both tests negative.
Project description:Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man5 GlcNAc2 consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.
Project description:Stage IV non-small cell lung cancer (NSCLC) exists on a spectrum, with a subset of patients presenting with oligometastatic disease involving only a limited number of distant sites. For these patients, local consolidative therapy (LCT) has been demonstrated to improve outcomes through ablation or cytoreduction of metastatic disease, as shown in an increasing number of randomized controlled trials. In particular, stereotactic ablative body radiation (SABR) has emerged as a feasible treatment modality for elimination of oligometastatic sites. This focused review examines the underlying biologic mechanisms and clinical data in support of SABR in the setting of oligometastatic NSCLC. Following a comprehensive evaluation of the pertinent retrospective, prospective, and anticipated trials to date, we summarize the evidence regarding patient selection, treatment safety, and technical considerations to provide guidance of this approach for clinicians.
Project description:A 35-year-old male patient was admitted to our hospital for urachal carcinoma with oligometastatic bone disease. He received a surgical resection through the umbilical area, urachal ligament and bladder dome (partial cystectomy) and adjuvant chemotherapy based on cisplatin-gemcitabine regimens together zoledronic acid with a good tolerance, no toxicity. Nine months after surgery, our patient presented no symptoms and the metastasis had been brought under control with no apparent signs of recurrence as assessed in a follow-up CT. To our knowledge, is the first case report of a urachal carcinoma with oligometastatic bone disease who received multimodal therapy, including surgery resection.
Project description:BackgroundIn certain malignancies, patients with oligometastatic disease benefit from radical ablative or surgical treatment. The SABR-COMET trial demonstrated a survival benefit for oligometastatic patients randomized to local stereotactic ablative radiation (SABR) compared to patients receiving standard care (SC) alone. Our aim was to determine the cost-effectiveness of SABR.Materials and methodsA decision model based on partitioned survival simulations estimated costs and quality-adjusted life years (QALY) associated with both strategies in a United States setting from a health care perspective. Analyses were performed over the trial duration of six years as well as a long-term horizon of 16 years. Model input parameters were based on the SABR-COMET trial data as well as best available and most recent data provided in the published literature. An annual discount of 3% for costs was implemented in the analysis. All costs were adjusted to 2019 US Dollars according to the United States Consumer Price Index. SABR costs were reported with an average of $11,700 per treatment. Deterministic and probabilistic sensitivity analyses were performed. Incremental costs, effectiveness, and cost-effectiveness ratios (ICER) were calculated. The willingness-to-pay (WTP) threshold was set to $100,000/QALY.ResultsBased on increased overall and progression-free survival, the SABR group showed 0.78 incremental QALYs over the trial duration and 1.34 incremental QALYs over the long-term analysis. Treatment with SABR led to a marginal increase in costs compared to SC alone (SABR: $304,656; SC: $303,523 for 6 years; ICER $1,446/QALY and SABR: $402,888; SC: $350,708 for long-term analysis; ICER $38,874/QALY). Therapy with SABR remained cost-effective until treatment costs of $88,969 over the trial duration (i.e. 7.6 times the average cost). Sensitivity analysis identified a strong model impact for ongoing annual costs of oligo- and polymetastatic disease states.ConclusionOur analysis suggests that local treatment with SABR adds QALYs for patients with certain oligometastatic cancers and represents an intermediate- and long-term cost-effective treatment strategy.