Introduction: Defects in the DNA damage response (DDR) drive the development of cancer by fostering DNA mutation but also provide cancer-specific vulnerabilities that can be exploited therapeutically. The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1.
Areas covered: We summarise the current stage of development of these novel DDR kinase inhibitors, and describe which predictive biomarkers might be exploited to direct their clinical use.
Expert opinion: Novel DDR inhibitors present promising candidates in cancer treatment and have the potential to elicit synthetic lethal effects. In order to fully exploit their potential and maximize their utility, identifying highly penetrant predictive biomarkers of single agent and combinatorial DDR inhibitor sensitivity are critical. Identifying the optimal drug combination regimens that could used with DDR inhibitors is also a key objective. 相似文献
To test if and how chemotherapy‐induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI‐PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation (“impossible”) generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%‐65% of patients; 76%‐78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%‐56% of them. In Group 3 strength reduction was observed in 49%‐50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials. 相似文献
An 11-year-old boy presented 2 days after a head injury with headache and vomiting. There were no neurological abnormalities. CT of the head demonstrated a large epidural haematoma and a cranial fracture. 相似文献
Persistent infection with high-risk human papillomaviruses (HPVs) is the greatest risk factor for the development of HPV-associated cancers. In this study rabbits bearing persistent and potentially malignant papillomas were used to test the efficacy of vaccination with a recombinant DNA and/or vesicular stomatitis virus (VSV) targeting the cottontail rabbit papillomavirus (CRPV) E6 protein. Immune responses were primed with either vector and boosted twice with the homologous or heterologous E6 vector. Over the course of 18 weeks, E6 vaccination reduced papilloma volumes to one third the volume in the controls, and the rabbits boosted with an heterologous vector tended to mount stronger responses. Small and medium-sized papillomas responded significantly but only slightly better than large papillomas. Finally the initial papilloma burden per rabbit, ranging from <100 mm3 to >1000 mm3, was not prognostic of antitumor efficacy. In summary both E6 vaccines elicited significant therapeutic immunity, and their sequential use tended to be advantageous. 相似文献
To compare physiological age-relatedness between dyskinesia (dystonia/choreoathetosis), dystonia and ataxia rating scale scores in healthy children.
Method
Three movement disorders specialists quantified dyskinetic-like features in healthy children (n = 52; 4–16 years) using the Dyskinesia Impairment Scale (DIS = DIS-choreoathetosis (DIS-C) + DIS-dystonia (DIS-D)). We compared the age-related regression coefficients of the DIS with data processed from previous studies on dystonia and ataxia rating scales (Burke-Fahn-Marsden Movement and Disability Scales (BFMMS and BFMDS) and Scale for Assessment and Rating of Ataxia (SARA), International Cooperative Ataxia Rating Scale (ICARS) and Brief Ataxia Rating Scale (BARS)).
Results
Dyskinetic scores were obtained in 79% (DIS); 65% (DIS-D) and 17% (DIS-C) versus dystonic and ataxic scores in 98% (BFMMS) and 89% (SARA/ICARS/BARS) of the children. Age-related DIS and DIS-D scores (B = ?0.90 and 0.77; p < 0.001) were correlated with age-related BFMMS scores (B = ?0.49; p<0.001; r = 0.87; p<0.001), whereas DIS-C scores were age-independent. Ataxic scores revealed stronger age-related regression coefficients than dyskinetic and dystonic scores (4–8 years; p<0.05).
Interpretation
In healthy children, comparison between physiological dyskinesia, dystonia and ataxia rating scale scores revealed: 1. inverse age-relatedness for dystonic and ataxic scores, but not for choreoathetotic scores, 2. interrelated dystonic DIS-D and BFMMS scores, 3. the strongest age-related expression by ataxic scores. In healthy children, these physiological movement disorder-like features are interpreted as an expression of the developing underlying motor centres. 相似文献
Hairy leukoplakia has been defined and confirmed as a specific oral mucosal marker for human immunodeficiency virus infection. Light microscopic findings include alteration of spinous layer cells, which contain nuclear chromatin abnormalities. Enlargement of spinous cells with ballooning degeneration is also characteristic. Ultrastructural morphology has defined the presence of large numbers of herpes-type virus particles within the intranuclear, cytoplasmic, and intercellular regions. Morphologically, the criteria of Epstein-Barr virus are satisfied. Southern blot analysis has confirmed the virus to be Epstein-Barr virus. Further hybridization analyses failed to show any evidence of human immunodeficiency virus or human papillomavirus in the lesions themselves. We conclude that hairy leukoplakia may represent an epithelial opportunistic Epstein-Barr virus infection. Finally, the production and shedding of Epstein-Barr virions into the oral cavity from the sites of hairy leukoplakia can occur separate from the usual tonsillar and oropharyngeal sites. 相似文献
Since the introduction of chemoradiotherapy with temozolomide as the new standard of care for patients with glioblastoma, there has been an increasing awareness of progressive and enhancing lesions on MRI, noted immediately after the end of treatment, which are not related to tumour progression, but which are a treatment effect. This so-called pseudoprogression can occur in up to 20% of patients who have been treated with temozolomide chemoradiotherapy, and can explain about half of all cases of increasing lesions after the end of this treatment. These lesions decrease in size or stabilise without additional treatments and often remain clinically asymptomatic. Additionally, there is evidence that treatment-related necrosis occurs more frequently and earlier after temozolomide chemotherapy than after radiotherapy alone. The mechanisms behind these events have not yet been fully elucidated, but the likelihood is that chemoradiotherapy causes a higher degree of (desired) tumour-cell and endothelial-cell killing. This increased cell kill might lead to secondary reactions, such as oedema and abnormal vessel permeability in the tumour area, mimicking tumour progression, in addition to subsequent early treatment-related necrosis in some patients and milder subacute radiotherapy reactions in others. In patients managed with temozolomide chemoradiotherapy who have clinically asymptomatic progressive lesions at the end of treatment, adjuvant temozolomide should be continued; in clinically symptomatic patients, surgery should be considered. If mainly necrosis is noted during surgery, continuation of adjuvant temozolomide is logical. Trials on the treatment of recurrent malignant glioma should exclude patients with progression within the first 3 months after temozolomide chemoradiotherapy unless histological confirmation of tumour recurrence is available. Further research is needed to establish reliable imaging parameters that distinguish between true tumour progression and pseudoprogression or treatment-related necrosis. 相似文献