Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Significance of lung contusion in mortality following polytrauma. Possibilities for therapeutic influence

Multiple trauma is often associated with blunt thoracic injuries. Especially lung contusion can result in respiratory insufficiency and therefore a higher mortality rate. In our prospective study comparing 8 multiple trauma patients with and without associated lung contusion, we found that respiratory function was already significantly disturbed (decrease of paO2/FiO2 and increase of AaDO2, a rise in extravascular lung water (EVLW) both early after trauma and also with a second peak following the 4th day. This group (LK) developed significantly more cases of respiratory distress (ARDS). The disturbance of respiratory function seen initially was interpreted as a consequence of the direct mechanical impact, leading to the formation of interstitial fluid and hematoma. The frequent development of ARDS in the LK-group probably results from a pronounced activation of cellular and humoral mechanisms and therefore an enforced injury of the pulmonary capillary bed. A significant increase of pulmonary infections or the development of sepsis was not seen in the LK-group and is probably not responsible for the higher ARDS-rate in this group.     

Effectiveness and Prognostic Factors of Radiotherapy for Painful Plantar Heel Spurs

BACKGROUND AND PURPOSE: The efficacy of radiation treatment (RT) for plantar heel pain has been reported repeatedly. Yet, the results referring to the pain relief rate, to long-term effects and prognostic factors are not consistent. In this paper, the effectiveness (pain relief rate and long-term results) and prognostic factors of RT for plantar heel pain have been investigated. PATIENTS AND METHODS: From January 2000 to October 2000, 62 patients (73 heels) with painful plantar heel spurs and a minimum pain history of 3 months were treated and evaluated in a prospective study. Mean age was 54 years (range 28-84 years). All patients were treated with a total dose of 5 Gy in seven fractions (= one series), given twice a week at a single-dose sequence of 0.25-0.25-0.5-1.0-1.0-1.0-1.0 Gy (10-MV photons, source-skin distance [SSD] 100 cm, direct portal, field size 12 x 17 cm). The mean duration of heel pain before RT was 26 weeks (= 6.5 months; range 3-120 months). By means of a visual analog scale (VAS) the patients had to self-assess the quantity of their heel pain once before, three times during and four times after RT at a longterm median follow-up of 28 and 40 months. Additionally, the patients had to assess their mechanical heel stress extent during RT. Effectiveness was estimated according to the patients' judgment of pain reduction. RESULTS: A significant reduction of heel pain extent measured by VAS has been observed already during the RT series (before RT: 6.3 +/- 1.5 vs. 3.8 +/- 2.1 at the end of RT; p < 0.001). 6 weeks after RT (FU 1) pain reduction (> 20%) was achieved in 60 heels (82.3%; n = 73), in 64 heels (91.4%; n = 70) after a mean follow-up of 28 months (FU 2), and in 61 heels (89.7%; n = 68) after a mean follow-up of 40 months (FU 3), respectively. Sufficient pain relief (> 80% compared to initial extent) was observed in 18/73 heels (24.6%) at FU 1 (FU 2: 42/70; 60.0%; FU 3: 37/68; 54.4%), including 13/73 heels (17.8%) with complete pain relief (FU 2: 39/70; 55.7%; FU 3: 36/68; 52.9%). Partial improvement (50-80% pain reduction) was observed in 27/73 heels (37.0%) at FU 1 (FU 2: 14/70; 20.0%; FU 3: 15/68; 22.1%), and minor partial improvement (20-50% pain reduction) in 15/73 heels (20.5%) at FU 1 (FU 2: 8/70; 11.4%; FU 3: 9/68; 13.2%), respectively. No change was seen in 13/73 heels (17.8%) at FU 1 (FU 2: 6/70; 8.6%; FU 3: 7/68; 10.3%). Older patients (p = 0.04) and patients who avoided heel stress during the period of RT (p < 0.01) demonstrated a better short-term response (FU 1); both effects were lost 28 and 40 months after RT. Moreover, significant differences in the extent of heel pain reduction by RT were observed in dependence on previous pain duration (at FU 2-3). CONCLUSION: The results confirm the high efficacy of RT in painful plantar spur and add new aspects to formerly published data concerning the time course of changes in heel pain reduction. Pain relief can be expected during and shortly after RT. In addition, the initial success can be transformed into effective long-term results > 2 years after RT; however, further improvement is not to be expected. As a new prognostic factor, the reduction of mechanical heel stress during RT may ameliorate the short-term results, whereas short heel pain history improves the long-term results. Especially for older patients, RT should be taken into consideration as primary treatment.     

The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors.

Members of the R7 subfamily of regulators of G-protein signaling (RGS) proteins (RGS6, RGS7, RGS9-2, and RGS11) are found in the mouse CNS. The expression of these proteins was effectively reduced in different neural structures by blocking their mRNA with antisense oligodeoxynucleotides (ODNs). This was achieved without noticeable changes in the binding characteristics of labeled beta-endorphin to opioid receptors. Knockdown of R7 proteins enhanced the potency of antinociception promoted by morphine and [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO)-both agonists at mu-opioid receptors. The duration of morphine analgesia was greatly increased in RGS9-2 and in RGS11 knockdown mice. The impairment of R7 proteins brought about different changes in the analgesic activity of selective delta agonists. Knockdown of RGS11 reduced [D-Ala(2)]deltorphin II analgesic effects. Those of RGS6 and RGS9-2 proteins caused [D-Ala(2)]deltorphin II to produce a smoothened time-course curve-the peak effect blunted and analgesia extended during the declining phase. RGS9-2 impairment also promoted a similar pattern of change for [D-Pen(2,5)]-enkephalin (DPDPE). RGS7-deficient mice showed an increased response to both [D-Ala(2)]deltorphin II and DPDPE analgesic effects. A single intracerebroventricular (i.c.v.) ED(80) analgesic dose of morphine gave rise to acute tolerance in control mice, but did not promote tolerance in RGS6, RGS7, RGS9-2, or RGS11 knockdown animals. Thus, R7 proteins play a critical role in agonist tachyphylaxis and acute tolerance at mu-opioid receptors, and show differences in their modulation of delta-opioid receptors.     

β受体阻断剂用于预防肝硬化患者出现胃食管静脉曲张

背景:非选择性β受体阻断剂能够降低门静脉压力和预防静脉曲张出血,但其能否预防静脉血管曲张尚不清楚。方法:对213例肝硬化门静脉高压患者犤最小门静脉压力梯度(H VPG)为6m m H g犦进行随机分组:其中108例接受噻吗洛尔(一种非选择性β受体阻断剂)治疗,105例接受安慰剂治疗。主     

Phenotype traits associated with different alleles at the RPS5 locus in Saccharomyces cerevisiae

Summary The RPS5 gene has been characterised through its ability to reduce invertase production by the SUC5 gene. In this paper we show that RPS5 acts by maintaining low levels of SUC5 mRNA. We also show that RPS5 acts on the SUC1 and SUC4 genes but not on SUC2 and SUC3, which are members of the SUC family. RPS5 also shows a pleiotropic effect on the amount of mitochondrial cytochromes.