Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy

Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild-type samples and a 17%-fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes.     

综合性ICU患者监护记录单临床应用的前瞻性研究

目的研究新时期综合ICU患者的临床监护记录单,以保证患者及护士使用过程的便利及安全。方法将我院ICU自2002年使用的“图标式ICU监护记录单”,在原表格的基础上根据综合ICU患者需要多系统监测的特点进行修订,主要以数字和符号表示形式形成新的护理记录表格,并采取对比的方法考证新旧两种表格的效用。结果两种表格各项指标比较：相同人数的护士分别填写两种不同表格所使用的时间分别是新表格平均（66±11）min,旧表格平均（97±10）min,每份表格的分数设为100分,护理质量检查小组检查的结果,新表格平均（97±2）分,旧表格平均（94±2）分,两组时间及分数比较差异有统计学意义（t=10．6263,4．0307;P〈0．01）;新旧表格使用合格率比较差异有统计学意义（90．12％比82．62％,x2=67．49,P〈0．01）。结论新的监护记录单更科学、更全面、简洁、更适合综合ICU不同种类的患者的记录要求,减轻护士工作量,减少记录时间,提高工作效率。     

Foot and leg problems are important determinants of functional status in community dwelling older people

Purpose.?To determine whether foot and leg problems are independently associated with functional status in a community sample of older people after adjusting for the influence of socio-demographic, physical and medical factors.

Method.?Data were analysed from the Health Status of Older People project, a population-based study involving a random sample of 1000 community-dwelling people aged 65?–?94 years (533 females, 467 males, mean age 73.4 years?±?5.87). A structured interview and brief physical examination were used to investigate the associations between self-reported foot and leg problems and functional status. Functional status was assessed using: (i) timed ‘Up & Go’ test, (ii) self-reported difficulty climbing stairs, (iii) self-reported difficulty walking one kilometer, (iv) self-reported difficulty performing instrumental activities of daily living (IADLs), and (v) self-reported history of one or more falls in the previous 12 months. These associations were then explored after adjusting for socio-demographic, physical and medical factors.

Results.?Thirty-six percent of the sample reported having foot or leg problems. Univariate analyses revealed that people with foot and leg problems were significantly more likely to exhibit poorer functional status in all parameters measured. After adjusting for socio-demographic, physical and medical factors, foot and leg problems remained significantly associated with impaired timed ‘Up & Go’ performance (OR?=?2.15, 95%CI 1.55?–?2.97), difficulty climbing stairs (OR?=?3.33, 95%CI 1.98?–?5.61), difficulty walking one kilometer (OR?=?3.13, 95%CI 2.09?–?4.69), and history of falling (OR?=?1.73, 95%CI 1.26?–?2.37).

Conclusions.?Foot and leg problems are reported by one in three community-dwelling people aged 65 years and older. Independent of the influence of age, gender, common medical conditions and other socio-demographic factors, foot and leg problems have a significant impact on the ability to perform functional tasks integral to independent living.     

Colonic motility diagnosis based on colonic pressure

Manometry of the alimentary tract is a valuable and widely used means to evaluate and diagnose the function of the alimentary tract. However, the measurement can be inconvenient due to the invasive method used, and the many factors affecting results. Research on colonic pressure data is even more insufficient. This paper deals with colonic pressure data via an improved method ensuring that pressure data of the whole colon is available. The data is analysed based on the learning vector quantization (LVQ) method. Testing results show that this method distinguishes the normal data and the abnormal data, consistently with the original diagnoses. This method can serve as an assistant diagnosis of colonic motility and contributes to further research on colonic motility based on pressure data.     

Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein- 1 alpha

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha with improved solution properties. We show here that it mobilizes stem cells into the peripheral blood. We investigated the mobilizing effects of BB-10010 on the numbers of circulating 8-day spleen colony-forming units (CFU-S8), CFU-S12, and progenitors with marrow repopulating ability (MRA). A single subcutaneous dose of BB-10010 caused a twofold increase in circulating numbers of CFU-S8, CFU-S12, and MRA 30 minutes after dosing. We also investigated the effects of granulocyte colony-stimulating factor (G- CSF) and the combination of G-CSF with BB-10010 on progenitor mobilization. Two days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA progenitors by 25.7-, 19.8-, and 27.7-fold. A single administration of BB-10010 after 2 days of G-CSF treatment increased circulating CFU-S8, CFU-S12, and MRA even further to 38-, 33-, and 100- fold. Splenectomy resulted in increased circulating progenitor numbers but did not change the pattern of mobilization. Two days of treatment with G-CSF then increased circulating CFU-S8, CFU-S12, and MRA by 64-, 69-, and 32-fold. A single BB-10010 administration after G-CSF treatment further increased them to 85-, 117-, and 140-fold, respectively, compared with control. We conclude that BB-10010 causes a rapid increase in the number of circulating hematopoietic progenitors and further enhances the numbers induced by pretreatment with G-CSF. BB- 10010 preferentially mobilized the more primitive progenitors with marrow repopulating activity, releasing four times the number achieved with G-CSF alone. Translated into a clinical setting, this improvement in progenitor cell mobilization may enhance the efficiency of harvest and the quality of grafts for peripheral blood stem cell transplantation.     

Surface antigens on malignant Sezary and T-CLL cells correspond to those of mature T cells

Tumor cells from eight adult patients with T-cell chronic malignancies were investigated with a series of monoclonal antibodies recognizing T- cell differentiation antigens. This series allowed definition of discrete subpopulations of mature T cells with functional specialization. All six patients with Sezary syndrome and one patient with T-chronic lymphocytic leukemia had cells with the same phenotype as normal helper/inducer T cells, whereas the other patient with T- chronic lymphocytic leukemia had cell with the same phenotype as normal cytotoxic/suppressor T cells. Some clinical manifestations observed in these patients may reflect retention of functional activities by their malignant cells.     

Audit of nutrition support for hematopoietic stem cell transplantation at a single institution

OBJECTIVE: To analyze experience with total parenteral nutrition (TPN) for hematopoietic stem cell transplantation (HSCT) at our institution compared with reports in the literature. PATIENTS AND METHODS: We reviewed medical records of 100 patients (53 men and 47 women) who underwent HSCT from 1992 to 2001. Data were abstracted on demographics, primary diagnosis, type of transplantation, myeloablative regimen, length of hospital stay, time to engraftment, 1- and 5-year survival, initiation and duration of TPN, and TPN-related complications. RESULTS: Seventy-one transplantations were autologous, 27 allogeneic, and 2 syngeneic. The median age of the patients was 51 years (range, 19-71 years). We initiated TPN when patients' oral caloric intake was less than 50% of their estimated needs (4 to 7 days after the start of myeloablative therapy; median, 1.2 days after HSCT; range, 8 days before HSCT to 13 days after HSCT). We discontinued TPN when oral intake was more than 50% of estimated needs (median duration, 16 days for autologous and 24 days for allogeneic transplantations, with the shortest duration in breast cancer patients and the longest duration in those treated with cyclophosphamide). Mean weight loss was less than 2%. No differences in patient characteristics, myeloablative regimen, or diagnosis were observed between patients who required and those who did not require TPN. Infection, hospital stay, time to engraftment, and mortality were comparable to published reports. CONCLUSION: In patients undergoing HSCT, TPN should not be initiated until oral caloric intake is less than 50% of estimated needs. During the period of inadequate oral intake, TPN maintains stable body weight with longer duration of support needed for patients undergoing allogeneic than for those undergoing autologous transplantations.     

Sleeping position and sudden infant death syndrome (SIDS): effect of an intervention programme to avoid prone sleeping

The proportion of prone sleeping among sudden infant death syndrome (SIDS) victims and infants in general, and the rate of SIDS were prospectively studied in the county of Hordaland, Norway, three years before (1987–89) and three years after (1990–92) a campaign to discourage prone sleeping. Before the campaign, 64% of random reference infants were put prone versus 8% after (p < 0.0001). Concurrently, the rate of SIDS decreased from 3.5 to 1.6 per 1000 live births (63 infants before and 30 after the campaign, p = 0.0002). Prone sleeping was not considered a statistically significant risk factor for SIDS before (OR 2.0,95% CI 0.8–4.5), but was highly significant (OR 11.3,95% CI 3.6–36.5) after the campaign. Prone sleeping is an important risk factor for SIDS, but the association may be missed in epidemiological studies if prone is the predominant sleeping position. Behaviour with regard to sleeping position may be changed rapidly by means of a simple campaign.     

The nasal mucosa in softwood exposed furniture workers

Recent reports suggest that softwood exposed woodworkers may have an increased incidence of sinonasal carcinoma. The present study was undertaken in order to evaluate the histological changes, especially the presence of possible precancerous lesions, in the nasal mucosa of furniture workers exclusively exposed to softwood. Histological examination of nasal biopsies from 44 furniture workers and 37 controls revealed a higher degree of metaplastic changes in the former group. In addition we observed four cases (9%) of dysplasia among softwood exposed workers. Nasal epithelial dysplasia is morphologically similar to dysplasia in other organs where the precancerous state of this lesion has been proved. Acceptance of nasal dysplasia as a precancerous lesion means that histological examination of biopsies is an appropriate tool in identifying occupational groups with an increased incidence of sinonasal carcinoma.     

Acute rejection in the elderly recipient: Influence of age in the outcome of kidney transplantation

Since the immune response in older recipientsis weaker they should be less likely to rejecta transplanted organ and should need lessaggressive immunosuppressive treatment. Our aimwas to record the incidence and severity ofepisodes of acute rejection (AR), estimate theinfluence of these events on graft survival ofelderly recipients (60) and to comparethese with that in younger ones.We performed 363 kidney transplants between1/94 and 12/98, and recorded clinical andimmunological data, incidence-severity of ARand cause of graft loss. Patients were dividedinto two groups, according to the age attransplantation: A (<60, n = 281/77.4%) and B( 60, n = 82/22.6%). The percentage ofaging recipients and mean age of donors andrecipients increased throughout the period.Although the incidence of ATN was higher in theolder group (29% vs.19%, p < 0.0001) thenumber of graft biopsies was equal in bothgroups. The incidence of AR was similar, 33.4%vs. 26.8%, pNS. The number of AR episodes perpatient was 0.44 and 0.41 respectively. Theseverity of AR was: Banff grade I: A (40.3%)/B (45.7%) pNS; grade II: A (44.1%)/B(48.57) pNS; grade III: A (15.5%)/B (5.7%)pNS. Younger recipients presented a higherlevel of panel-reactive antibodies (PRA) (4.3%vs. 2.07%, p = 0.01). One-year patient survivalwas 96%/91% (p<0.05) and graft survivalwas 81%/78% (pNS) respectively.The age of recipient does not seem to haveinfluenced the incidence-severity of AR or thegraft survival. Thus immunosuppression shouldbe individualised for each patient and shouldnot depend on the age at transplantation.