Cell Cycle Proteins Predict Recurrence in Stage II and III Colon Cancer

Purpose

To investigate the prognostic value of multiple cell cycle-associated proteins in a large series of stage II and III colon cancers.

Methods

From formalin-fixed, paraffin-embedded tumor samples of 386 patients with stage II and III colon cancer, DNA was isolated and tissue microarrays were constructed. Tissue microarray slides were immunohistochemically stained for p21, p27, p53, epidermal growth factor receptor, Her2/Neu, β-catenin, cyclin D1, Ki-67, thymidylate synthase, and Aurora kinase A (AURKA). Polymerase chain reaction–based microsatellite instability analysis was performed to allow for stratification of protein expression by microsatellite instability status.

Results

Overall, low p21, high p53, low cyclin D1, and high AURKA expression were significantly associated with recurrence (P = 0.01, P < 0.01, P = 0.04, and P < 0.01, respectively). In stage II patients who did not receive adjuvant chemotherapy (n = 190), significantly more recurrences were observed in case of low-p21 and high-p53-expressing tumors (P < 0.01 and P = 0.03, respectively). In stage III patients who did not receive chemotherapy, high p53 expression was associated with recurrence (P = 0.02), and in patients who received chemotherapy, high AURKA expression was associated with relapse (P < 0.01). In patients with microsatellite stable tumors, high levels of p53 and AURKA were associated with recurrence (P = 0.01 and P < 0.01, respectively). Multivariate analysis showed p21 (odds ratio 1.6, 95% confidence interval 0.9–2.8) and AURKA (odds ratio 2.7, 95% confidence interval 1.3–5.6) to be independently associated with disease recurrence.

Conclusions

p21, p53, cyclin D1, and AURKA could possibly be used as prognostic markers to identify colon cancer patients with high risk of disease recurrence.

     

Oxidative stress and BDNF as possible markers for the severity of crack cocaine use in early withdrawal

Rationale

An important goal of addiction research is to discover neurobiological markers that could predict the severity of addiction and help to determine appropriate treatment. Brain-derived neurotrophic factor (BDNF) and thiobarbituric acid reactive substances (TBARS) are being related to cerebral plasticity and impairment caused by substance abuse.

Objectives

This study aims to evaluate alteration of TBARS and BDNF levels among crack cocaine users during early drug withdrawal and its relationship to severity of drug use.

Methods

Forty-nine adults crack cocaine users were recruited at a public psychiatric hospital with a specialized addiction treatment unit. Blood sample was collected at intake and discharge for the analysis of TBARS and BDNF measures. Information about drug use was assessed by the Addiction Severity Index 6th Version (ASI-6). Detailed information about crack cocaine use was obtained through the “Profile of the crack cocaine user.” Severity of crack use was estimated using information from age of first crack use, years of crack use, and crack rocks used in the previous 30 days.

Results

There is a positive correlation between TBARS levels and severity of crack cocaine use (R?=?0.304, p?=?0.04) and a negative correlation between BDNF and severity of crack cocaine use (R?=??0.359, p?=?0.01) at discharge. Also, we found an inverse correlation between TBARS and BDNF levels (R?=??0.294, p?=?0.004) at discharge.

Conclusions

Our findings suggest that BDNF and TBARS could be possible markers for the severity of drug use. Further studies may show how those markers could be related to staging, prognosis, and treatment in crack cocaine dependence.     

Risk behaviors for HCV- and HIV-seroprevalence among female crack users in Porto Alegre, Brazil

Several studies have shown a high prevalence of HIV-seropositive status among crack users, though most refer to North American populations. Few studies evaluate HCV prevalence among female crack users. In addition, there is a particular lack of data about risk behaviors and HIV/HCV prevalence in this population around the world. In order to ascertain the HIV/HCV serostatus and associated risk behaviors for infection of female crack users of Porto Alegre, Brazil. A cross-sectional study of a convenience sample of 73 current female crack users was conducted. Subjects answered NIDA’s Risk Behavior Assessment and an AIDS Information Questionnaire. In addition, blood was collected from subjects for HIV/HCV tests. The overall prevalence of HIV was 37.0%; HCV seroprevalence was 27.7%; of 15.1% the sample was co-infected with HIV and HCV. Four years of schooling or fewer (OR 4.72–CI 95%; 1.49–14.99) and having three or more HIV tests in one’s lifetime (OR 4.26–CI 95% (1.29–14.04)) were associated with HIV infection (after multivariate logistic regression). The single greatest risk factor for HCV infection was having 4 years of schooling or fewer (OR 4.51–CI 95%; 1.18–17.27). We found a very high prevalence of HIV and HCV infection among female crack users, and low education was the most significant risk factor associated with both infections.     

Influence of smoking habits on the frequencies of structural and numerical chromosomal aberrations in human peripheral blood lymphocytes using the fluorescence in Situ hybridization (FISH) technique

The influence of smoking on the spontaneous frequencies of unstableand stable chromosomal aberrations in stimulated lymphocytesusing conventional Giemsa staining and flurescence in situ hybridization(FISH) was studied. The study groups consisted of 12 smokersand 30 nonsmokers. The frequency of translocations was determinedusing nine different chromosome-specific DNA libraries, representing–50% of the human genome, usually in a combination oftwo to three chromosomes in one cocktail. Using DNA librariesfor specific chromosomes and FISH also made it possible to detectaneuploid cells. No significant difference was observed betweensmokers and nonsmokers in the frequencies of unstable and stabletype of chromosomal aberrations. However, a significantly (P     

A pilot study on the influence of a corticotropin (4-9) analogue on Vinca alkaloid-induced neuropathy.

In a randomized, double-blind, placebo-controlled pilot study, we examined the effect of Org 2766--a corticotropin (4-9) analogue--on neurotoxicity in 28 patients with lymphoma who were treated with combination chemotherapy containing Vinca alkaloids (vincristine and vinblastine). The patients received a total dose of 12 mg of vincristine in the case of non-Hodgkin's lymphoma and a total dose of 16 mg of vincristine in the case of Hodgkin's disease. Moreover, the patients with Hodgkin's disease received a mean total dose of 84 mg of vinblastine. Subcutaneous injections of 2 mg of Org 2766 or placebo were administered to patients with non-Hodgkin's lymphoma on days 1 and 10 of each chemotherapy course and to patients with Hodgkin's disease on days 1 and 8 of each chemotherapy course. The first injection was always given before the administration of vincristine. Assessment of neurologic symptoms and signs and measurement of sensory thresholds (vibration sense and temperature sense) were performed on day 1 of the first, fourth, and sixth (or eighth) courses and 6 weeks after cessation of chemotherapy. Thirteen patients (mean age, 44.7 years) received Org 2766 and 15 patients (mean age, 54.7 years) received placebo. More symptoms occurred in the placebo group, but only numbness and autonomic complaints occurred significantly more often in the placebo group. Motor deficit and sensory disturbances were more severe and also occurred significantly more often in the placebo group. There was no difference with respect to reflex examination findings and sensory thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression

Removal of colorectal adenomas is an effective strategy to reduce colorectal cancer (CRC) mortality rates. However, as only a minority of adenomas progress to cancer, such strategies may lead to overtreatment. The present study aimed to characterize adenomas by in-depth molecular profiling, to obtain insights into altered biology associated with the colorectal adenoma-to-carcinoma progression. We obtained low-coverage whole genome sequencing, RNA sequencing and tandem mass spectrometry data for 30 CRCs, 30 adenomas and 18 normal adjacent colon samples. These data were used for DNA copy number aberrations profiling, differential expression, gene set enrichment and gene-dosage effect analysis. Protein expression was independently validated by immunohistochemistry on tissue microarrays and in patient-derived colorectal adenoma organoids. Stroma percentage was determined by digital image analysis of tissue sections. Twenty-four out of 30 adenomas could be unambiguously classified as high risk (n = 9) or low risk (n = 15) of progressing to cancer, based on DNA copy number profiles. Biological processes more prevalent in high-risk than low-risk adenomas were related to proliferation, tumor microenvironment and Notch, Wnt, PI3K/AKT/mTOR and Hedgehog signaling, while metabolic processes and protein secretion were enriched in low-risk adenomas. DNA copy number driven gene-dosage effect in high-risk adenomas and cancers was observed for POFUT1, RPRD1B and EIF6. Increased POFUT1 expression in high-risk adenomas was validated in tissue samples and organoids. High POFUT1 expression was also associated with Notch signaling enrichment and with decreased goblet cells differentiation. In-depth molecular characterization of colorectal adenomas revealed POFUT1 and Notch signaling as potential drivers of tumor progression.     

Identification of enterohemorrhagic Escherichia coli O26:H- genes required for intestinal colonization in calves

Enterohemorrhagic Escherichia coli (EHEC) infections in humans are an important public health problem and are commonly acquired via contact with ruminant feces. The serogroups that are predominantly associated with human infection in the United States and Europe are O157 and O26. Serotypes O157:H7 and O26:H- differ in their virulence and tissue tropism in calves and therefore may colonize calves by distinct mechanisms. The mechanisms underlying EHEC intestinal colonization and pathogenesis are poorly understood. Signature-tagged mutagenesis was used to identify 59 genes of EHEC O26:H- that are required for the intestinal colonization of calves. Our results indicate important roles for locus of enterocyte effacement (LEE)-encoded type III secreted proteins in intestinal colonization. In addition, colonization is facilitated by cytotoxins, putative type III secreted proteins unlinked to the LEE, a putative fimbrial operon, and numerous genes involved in central metabolism and transport and genes of unknown function. Our data also imply that the elaboration of type I fimbriae by EHEC O26:H- is disadvantageous for persistence within the bovine intestines. These observations have important implications for the design of vaccines to control these important zoonotic pathogens.     

Intra-Articular Hyaluronic Acid Injections Less Than 6 Months Before Total Hip Arthroplasty: Is It Safe? A Retrospective Cohort Study in 565 Patients

BackgroundIntra-articular hyaluronic acid (IAHA) can be injected into an osteoarthritic hip joint to reduce pain and to improve functionality. Several studies report IAHA to be safe, with minor adverse effects that normally disappear spontaneously within a week. However, intra-articular corticosteroids prior to total hip arthroplasty (THA) have been associated with increased infection rates. This association has never been investigated for IAHA and THA. We aimed to assess the influence of IAHA on the outcome of THA, with an emphasis on periprosthetic joint infection (PJI).MethodsAt a mean follow-up of 52 months (±18), we compared complication rates, including superficial and deep PJIs, of THA in patients who received an IAHA injection ≤6 months prior to surgery (injection group) with that of patients undergoing THA without any previous injection in the ipsilateral hip (control group). One hundred thirteen patients (118 hips) could be retrospectively included in the injection group, and 452 patients (495 hips) in the control group.ResultsNo differences in baseline characteristics nor risk factors for PJI between the 2 groups were found. The clinical outcomes in terms of VAS pain scores (1.4 vs 1.7 points, P = .11), modified Harris Hip Scores (77 vs 75 points, P = .09), and Hip disability and Osteoarthritis Outcome Scores (79 vs 76 points, P = .24) did not differ between the injection group and the control group. Also, complications in terms of persistent wound leakage (0% vs 1.2%, P = .60), thromboembolic events (0% vs 0.6%, P = 1.00), periprosthetic fractures (1.7% vs 1.2%, P = .65), and dislocations (0% vs 0.4%, P = 1.00) did not differ. However, in the injection group there was a higher rate of PJIs (4% vs 0%, P < .001) and postoperative wound infections (9% vs 3%, P = .01), compared to the control group.ConclusionOur findings suggest that IAHA performed 6 months or less prior to THA may pose a risk for increased rates of PJI. We recommend refraining from performing THA within 6 months after IAHA administration.