135 research outputs found
The centromeric/nucleolar chromatin protein ZFP-37 may function to specify neuronal nuclear domains
Murine ZFP-37 is a member of the large family of C2H2 type zinc finger
proteins. It is characterized by a truncated NH2-terminal
Kruppel-associated box and is thought to play a role in transcriptional
regulation. During development Zfp-37 mRNA is most abundant in the
developing central nervous system, and in the adult mouse expression is
restricted largely to testis and brain. Here we show that at the protein
level ZFP-37 is detected readily in neurons of the adult central nervous
system but hardly in testis. In brain ZFP-37 is associated with nucleoli
and appears to contact heterochromatin. Mouse and human ZFP-37 have a
basic histone H1-like linker domain, located between KRAB and zinc finger
regions, which binds double-stranded DNA. Thus we suggest that ZFP-37 is a
structural protein of the neuronal nucleus which plays a role in the
maintenance of specialized chromatin domains
Chromatin jets define the properties of cohesin-driven in vivo loop extrusion
Complex genomes show intricate organization in three-dimensional (3D) nuclear space. Current models posit that cohesin extrudes loops to form self-interacting domains delimited by the DNA binding protein CTCF. Here, we describe and quantitatively characterize cohesin-propelled, jet-like chromatin contacts as landmarks of loop extrusion in quiescent mammalian lymphocytes. Experimental observations and polymer simulations indicate that narrow origins of loop extrusion favor jet formation. Unless constrained by CTCF, jets propagate symmetrically for 1-2 Mb, providing an estimate for the range of in vivo loop extrusion. Asymmetric CTCF binding deflects the angle of jet propagation as experimental evidence that cohesin-mediated loop extrusion can switch from bi- to unidirectional and is controlled independently in both directions. These data offer new insights into the physiological behavior of in vivo cohesin-mediated loop extrusion and further our understanding of the principles that underlie genome organization
Конкуренція університетів: світовий досвід і українські реалії
Досліджено процеси конкуренції вищих навчальних закладів; обґрунтовано основні критерії формування рейтингів університетів; виявлено взаємозв’язок між високим рейтингом університету і показником його елітності; розкрито значення капіталізації в конкурентних перевагах вищих навчальних закладів; визначено роль елітних університетів у постіндустріальному розвитку суспільства.Исследованы процессы конкуренции высших учебных заведений; обоснованы основные критерии формирования рейтингов университетов; показана взаимосвязь между высоким рейтингом университета и показателем его элитности; раскрыто значение капитализации в конкурентных преимуществах высших учебных заведений; определена роль элитных университетов в постиндустриальном развитии общества.The processes of competition of universities are studi ed, proved the main criteria for the formation of university rankings, found the relationship between highly-rated university and the rate of its elite, disclosed the value of capitalization in the competitive advantages of higher education institutions, and determined the role of elite universities in the post-industrial development
The Effect of Histopathological Growth Patterns of Colorectal Liver Metastases on the Survival Benefit of Adjuvant Hepatic Arterial Infusion Pump Chemotherapy
Background: Histopathological growth patterns (HGPs) are a prognostic biomarker in colorectal liver metastases (CRLM). Desmoplastic HGP (dHGP) is associated with liver-only recurrence and superior overall survival (OS), while non-dHGP is associated with multi-organ recurrence and inferior OS. This study investigated the predictive value of HGPs for adjuvant hepatic arterial infusion pump (HAIP) chemotherapy in CRLM. Methods: Patients undergoing resection of CRLM and perioperative systemic chemotherapy in two centers were included. Survival outcomes and the predictive value of HAIP versus no HAIP per HGP group were evaluated through Kaplan–Meier and Cox regression methods, respectively. Results:We included 1233 patients. In the dHGP group (n = 291, 24%), HAIP chemotherapy was administered in 75 patients (26%). In the non-dHGP group (n = 942, 76%), HAIP chemotherapy was administered in 247 patients (26%). dHGP was associated with improved overall survival (OS, HR 0.49, 95% CI 0.32–0.73, p < 0.001). HAIP chemotherapy was associated with improved OS (HR 0.61, 95% CI 0.45–0.82, p < 0.001). No interaction could be demonstrated between HGP and HAIP on OS (HR 1.29, 95% CI 0.72–2.32, p = 0.40).Conclusions: There is no evidence that HGPs of CRLM modify the survival benefit of adjuvant HAIP chemotherapy in patients with resected CRLM.</p
Ectopic A-lattice seams destabilize microtubules
Natural microtubules typically include one A-lattice seam within an otherwise helically symmetric B-lattice tube. It is currently unclear how A-lattice seams influence microtubule dynamic instability. Here we find that including extra A-lattice seams in GMPCPP microtubules, structural analogues of the GTP caps of dynamic microtubules, destabilizes them, enhancing their median shrinkage rate by >20-fold. Dynamic microtubules nucleated by seeds containing extra A-lattice seams have growth rates similar to microtubules nucleated by B-lattice seeds, yet have increased catastrophe frequencies at both ends. Furthermore, binding B-lattice GDP microtubules to a rigor kinesin surface stabilizes them against shrinkage, whereas microtubules with extra A-lattice seams are stabilized only slightly. Our data suggest that introducing extra A-lattice seams into dynamic microtubules destabilizes them by destabilizing their GTP caps. On this basis, we propose that the single A-lattice seam of natural B-lattice MTs may act as a trigger point, and potentially a regulation point, for catastrophe
Salvage treatment for recurrences after first resection of colorectal liver metastases: the impact of histopathological growth patterns
The majority of patients recur after resection of colorectal liver metastases (CRLM). Patients with CRLM displaying a desmoplastic histopathological growth pattern (dHGP) have a better prognosis and lower probability of recurrence than patients
with non-dHGP CRLM. The current study evaluates the impact of HGP type on the pattern and treatment of recurrences after
first resection of CRLM. A retrospective cohort study was performed, including patients with known HGP type after complete
resection of CRLM. All patients were treated between 2000 and 2015. The HGP was determined on the CRLM resected at
first partial hepatectomy. The prognostic value of HGPs, in terms of survival outcome, in the current patient cohort were
previously published. In total 690 patients were included, of which 492 (71%) developed recurrent disease. CRLM displaying
dHGP were observed in 103 patients (21%). Amongst patients with dHGP CRLM diagnosed with recurrent disease, more
liver-limited recurrences were seen (43% vs. 31%, p=0.030), whereas patients with non-dHGP more often recurred at multiple locations (34% vs. 19%, p=0.005). Patients with dHGP CRLM were more likely to undergo curatively intended local
treatment for recurrent disease (adjusted odds ratio: 2.37; 95% confidence interval (CI) [1.46–3.84]; p<0.001) compared
to patients with non-dHGP. The present study demonstrates that liver-limited disease recurrence after complete resection o
The Disease-Free Interval Between Resection of Primary Colorectal Malignancy and the Detection of Hepatic Metastases Predicts Disease Recurrence But Not Overall Survival
Introduction. The disease-free interval (DFI) between
resection of primary colorectal cancer (CRC) and diagnosis
of liver metastases is considered an important prognostic
indicator; however, recent analyses in metastatic CRC
found limited evidence to support this notion.
Objective. The current study aims to determine the
prognostic value of the DFI in patients with
resectable colorectal liver metastases (CRLM).
Methods. Patients undergoing first surgical treatment of
CRLM at three academic centers in The Netherlands were
eligible for inclusion. The DFI was defined as the time
between resection of CRC and detection of CRLM. Baseline characteristics and Kaplan–Meier survival estimates
were stratified by DFI. Cox regression analyses were performed for overall (OS) and disease-free survival (DFS),
with the DFI entered as a continuous measure using a
restricted cubic spline function with three knots.
Results. In total, 1374 patients were included. Patients
with a shorter DFI more often had lymph node involvement
of the primary, more frequently received neoadjuvant
chemotherapy for CRLM, and had higher number of
CRLM at diagnosis. The DFI significantly contributed to
DFS prediction (p =0.002), but not for predicting OS
(p =0.169). Point estimates of the hazard ratio (95% confidence interval) for a DFI of 0 versus 12 months and 0
versus 24 months were 1.284 (1.114–1.480) and 1.444
(1.180–1.766), respectively, for DFS, and 1.111
(0.928–1.330) and 1.202 (0.933–1.550), respectively, for
OS.
Conclusion. The DFI is of prognostic value for predicting
disease recurrence following surgical treatment of CRLM,
but not for predicting OS outcomes
Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases
Abstract
Background In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns
(HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by
angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature.
Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared
to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values
for the determination of the predominant HGP. We have now investigated the
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