Otherwise variable "x" gets printed that as we found out contains the previous line. Notice that this one-liner uses a ternary operator "foo? The "print" statement then prints this next line. In this case the last line gets printed itself. This one-liner uses a feature of extended regular expressions that support the or alternation meta-character.
Only the lines that contain one or more of them get matched and printed. This one-liner uses a regular expression "AAA. CCC" to print lines. This one-liner uses the "length" function. This function is defined as "length [str] " - it returns the length of the string "str". For historical reasons, parenthesis at the end of "length" can be omitted. This one-liner is almost byte-by-byte equivalent to the previous one.
Here it tests if the length if line less than 64 characters. If it is, Awk prints it out. Otherwise nothing gets printed. This one-liner uses a pattern match in form 'pattern1, pattern2' that is called "range pattern".
It matches all the lines starting with a line that matches "pattern1" and continuing until a line matches "pattern2" inclusive. This one-liner also uses a range pattern in format "pattern1, pattern2". The first pattern means "the current line is 8th" and the second pattern means "the current line is 12th".
This one-liner prints lines between these two patterns. This one-liner tests to see if current line is number This one-liner forces Awk to quit after line number 52 is printed. Further, current treatment relevant molecular stratification of GB mainly depends on the methylation status of the O 6 -methylguanine methyltransferase MGMT -promoter.
Consequently, tumors with methylated MGMT promoter generally respond better to temozolomide treatment whereas MGMT expression in tumors with unmethylated gene promoter is a major mechanism of resistance and indicator for poor prognosis [ 15 , 16 , 46 ].
Many novel approaches to improve GB therapy rely on targeting specifically altered signal transduction cascades. However, these so called targeted therapies, including those targeting EGFR, thus far, have failed to show any benefit in GB treatment despite rational target selection and availability of potent drugs opening the quest for predictive biomarkers [ 39 , 52 ].
PRASphosphorylation correlated with shorter time to progression in a smaller GB patient cohort [ 8 ]. Another study in low grade glioma found a trend towards shorter survival in tumors with higher phospho-PRAS40 levels; however, statistical significance was not reached [ 29 ]. MTORC1 additionally integrates signals from the cellular energy status including oxygen availability [ 4 ], amino acid availability [ 2 ] and direct ATP content of the cell [ 20 ].
RPS6 phosphorylation has been discovered many years ago, still its molecular and physiological effects especially with regard to the phosphorylation of the different serine sites are currently still under investigation [ 31 ]. RPS6 has several mTORC1-dependent phosphorylation sites including serines at position and as well as the highly specific position and Fig.
Cellular lysates were analyzed by immunoblot with antibodies as indicated. It has shown promising results as a targeted therapy in the treatment of high grade gliomas in phase II studies [ 3 ] and pediatric brain stem gliomas [ 28 , 57 ]. The trial was negative, and a benefit of nimotuzumab treatment was apparent neither in the whole population studied nor in patients with EGFR amplification.
A post-hoc analysis of subgroups, however, revealed a trend for improved survival for MGMT unmethylated patients with residual tumor when treated with nimotuzumab PFS 6. This unplanned subgroup analysis, however, included only 28 patients and failed to reach statistical significance. The results of several recent trials suggest that for an effective targeted therapy, appropriate patients need to be identified [ 56 ]. With regard to signal transduction inhibitors it is plausible that genetic heterogeneity in GBs is also reflected by different degrees of dependence on certain signaling cascades [ 32 ].
Furthermore, we describe a trend for a predictive value of RPS6 phosphorylation in all patients irrespective of MGMT promoter methylation status. Nimotuzumab as well as the corresponding placebo control solution were provided by Oncoscience Wedel, Germany. Nimotuzumab is an IgG subtype 1 kappa with a molecular weight of Immunoblot was performed as described previously [ 14 ]. A chemiluminescence solution was used for detection [ 50 ].
NCT cohort included patients with GB [ 55 ]. This open label, randomised phase III study was approved by the central and local ethics review boards. Informed consent was obtained from all patients. In case of availability, we obtained tissue sections from these tumors for further immunohistochemistry.
Applied statistical test methods are either mentioned in the figure legend or in the flow content. For dichotomized univariate survival analyses we performed a median split to obtain a high and low group with regard to the investigated factor. The high group includes specimen with values above median, the low group includes specimen with median or below. Both substances caused effective inhibition of EGFR downstream signal transduction indicated by a similar degree of reduction in phosphorylation of the corresponding target proteins PRAS40 as well as RPS6 in an immunoblot experiment Fig.
Besides the actual GB tumor cells, GAMs can account for a relevant fraction of intratumoral cells and potentially influence signal transduction of cancer cells or constitute a potential source of mTORC1 or AKT signaling. GB necrosis occurs where demand exceeds supply of the fast growing tumor cells and the perinecrotic area is where nutrient and oxygen deprivation are most severe within the tumor. Interestingly, P-RPS6 as a target of mTORC1 was increased in necrotic tumors potentially indicating a defective nutrient sensing as a cause of increased necrosis [ 50 ] Fig.
Histological characterization of the patient cohort. P and r 2 values as indicated. However, with only 7 cases of vIII mutation in our cohort, the number was too small to derive any conclusions in this regard.
While necrosis as a surrogate of hypoxia or ischemia is a common histological feature in GB, a more outspread or increased necrosis extent or hypoxia could indicate a particularly aggressive tumor subtype. A relationship between patient survival and intratumoral hypoxia has e. EGFR signaling is known to promote many components of a more aggressive tumor phenotype and P-PRAS40 has been reported as an independent prognostic marker with regard to time to progression in a small glioma cohort [ 8 ].
We have previously shown that inhibition of EGFR or mTORC1 signal transduction can protect human glioblastoma cells from hypoxia-induced cell death [ 38 , 45 ]. Using a median split, we dichotomized tumors into two groups high and low Additional file 1 : Figure S1.
Within the group of above median value necrotic tumors, nimotuzumab treatment resulted in a slight trend towards improved survival, whereas no trend was detectable in below or median value necrotic tumors Fig. Even though P-PRAS40 and P-RPS6 were not associated with patient survival in the treatment arms Table 1 , tumors with activated downstream signaling might define a patient subgroup more addicted to EGFR signaling and thus more prone to respond to nimotuzumab.
In contrast in P-RPS6 high tumors, we observed a clear trend towards improved survival when nimotuzumab treatment was administered Fig. Survival analyses depending on treatment in histological subgroups. P values were calculated using the Wilcoxon test. When considering only the MGMT unmethylated cohort, the clear trend in favor of nimotuzumab therapy already detectable in the whole cohort regardless of MGMT promoter methylation status, now became significant when using a median split for P-RPS6 in tumors with above median value p value of 0.
Also, there was a trend towards an efficacy of nimotuzumab in MGMT promoter unmethylated tumors with above median extent of necrosis Fig. Survival analyses depending on treatment in histological subgroups for the MGMT-promoter unmethylated and methylated tumor cohort.
In patients treated with nimotuzumab, an above median expression of P-RPS6 was associated with improved survival Fig. The 8th Infantry Division's order of battle on October 31, , was as follows: .
From Wikipedia, the free encyclopedia. Division ; in and from August 2, , 8th Infantry Division 8. Army Corps IV. The German Army on the Somme: - Barnsley: Pen and Sword Books Ltd. List of Divisions List of Corps. Categories : Infantry divisions of Germany in World War I Military units and formations established in Military units and formations disestablished in Less successful were his many Opera and Singspiel projects. On the other hand, some of his most popular Lieder , like " Gretchen am Spinnrade ," were based on texts written for the theatre.
D , Music for Zauberspiel Die Zauberharfe for tenor, six spoken roles, mixed choir and orchestra , in three acts: Overtures to the first and third acts, and thirteen numbers; Overture to the first act known as the "Rosamunde" Overture, also used in D D 11 , Singspiel Der Spiegelritter for five sopranos, three tenors, four basses, mixed choir and orchestra ?
D , Singspiel Adrast for soprano, tenor, bass, men's choir and orchestra , in two or three acts? D , Singspiel Fernando for two sopranos, tenor, two basses, one spoken role and orchestra , in one act: seven numbers. D , Singspiel Claudine von Villa Bella for two sopranos, two tenors, two basses, mixed choir and orchestra , in three acts; incomplete — Act I: Overture and eight numbers, is extant, as well as one number from Act II and one number from Act III; remaining numbers were written, but are now lost.
D , Singspiel Die Freunde von Salamanka for three sopranos, three tenors, six basses, mixed choir and orchestra , in two acts: Overture and eighteen numbers.
D , Opera Sakuntala for fourteen sopranos, three altos, five tenors, nine basses, mixed choir and orchestra , also appears as "Sakontala" or "Sacontala"; in three acts; unfinished — sketches of eleven numbers from Acts I and II are extant.
D , Opera Alfonso und Estrella for two sopranos, two tenors, bass, two baritones, mixed choir and orchestra —, in three acts: Overture and thirty-four numbers. D , Opera Fierabras for three sopranos, three tenors, three basses, baritone, one spoken role, mixed choir and orchestra , also appears as "Fierrabras"; in three acts: Overture and twenty-three numbers; first published as Op.The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunction .