Input of microenvironmental regulation on colorectal cancer: Role of the CCN family

Colorectal cancer(CRC)is a major health problem causing significant morbidity and mortality.Previous results from various studies indicate that CRC tumorigenicity encompasses tumor microenvironment,emphasizing the complex interacting network between cancer cells and nearby host cells,which triggers diverse signaling pathways to promote the growth and spread ofcancer cells.The CCN family proteins share a uniform modular structure,mediating a variety of physiological functions,including proliferation,apoptosis,migration,adhesion,differentiation,and survival.Furthermore,CCN proteins are also involved in CRC initiation and development.Many studies have shown that CCN members,such as CCN1,CCN2,CCN3,Wnt-induced secreted protein(WISP)-1,WISP-2,and WISP-3,are dysregulated in CRC,which implies potential diagnostic markers or therapeutic targets clinically.In this review,we summarize the research findings on the role of CCN family proteins in CRC initiation,development,and progression,highlighting their potential for diagnosis,prognosis,and therapeutic application.     

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.Essential tremor is one of the most frequent movement disorders in humans (1). It is characterized primarily by postural or kinetic tremor of the arms and hands, but head, legs, voice, and other regions of the body may also be affected (2). The worldwide prevalence is 0.9%, increasing to more than 4% in elderly populations (1). Familial essential tremor is genetically heterogeneous. Genetic linkage studies of multiply affected families revealed three genomic regions segregating with the condition, on chromosomes 3q13 [ETM1; Online Mendelian Inheritance in Man (OMIM) 190300], 2p22-24 (ETM2; OMIM 602134), and 6p23 (ETM3; OMIM 611456) (3–5). No clearly causal mutations have been identified in these regions, although the common variant DRD3 p.S9G in the ETM1 region has been proposed as a risk factor and HS1BP3 p.A265G in the ETM2 region appeared in two multiply affected families (6, 7). Genomewide association studies of essential tremor reported associations with common variants in an intron of LINGO1 and in an intron of SLC1A2 (8–10). Recently, DNAJC13 p.N855S, which had been identified in Parkinson disease patients, was also found in two unrelated patients with essential tremor (11). Nonsense mutation p.Q290X in the RNA-binding protein FUS was identified by whole exome sequencing in a large family with essential tremor (ETM4; OMIM 614782) (12). Screening other subjects with essential tremor for FUS revealed two rare missense variants, suggesting that mutations in FUS explain a subset of cases with the condition (13, 14).In this study, we examined a six-generation family segregating essential tremor, and in multiple relatives, essential tremor as a feature of Parkinson disease. We carried out whole exome sequencing of genomic DNA from three severely affected family members and subsequent pedigree analysis to identify the genetic basis of essential tremor and Parkinson disease in the family.     

Effects of thrice weekly nocturnal hemodialysis on arterial stiffness

ObjectiveIn this study, we compared the changes in arterial stiffness in chronic hemodialysis patients treated with 8-h vs. 4-h thrice weekly in-center hemodialysis.MethodsSixty prevalent chronic hemodialysis patients assigned to 8-h nocturnal in-center thrice weekly HD (NHD) and 60 control cases assigned to 4-h thrice weekly conventional HD (CHD) were followed for one year. Radial–carotid pulse wave velocity, augmentation index and echocardiography were performed at baseline and 12^th month.ResultsMean age of the patients was 49 ± 11 years, 30.8% were female, 27.5% had diabetes mellitus and mean dialysis vintage was 57 ± 47 months. Baseline demographical, clinical and laboratory parameters were similar between groups. During a mean follow-up of 15.0 ± 0.1 months, blood pressure remained similar in both groups while the number of mean daily anti-hypertensive substances decreased in the NHD group. In the NHD group, time-averaged serum phosphorus and calcium–phosphorus product were lower than the CHD group. Pulse wave velocity and augmentation index decreased in the NHD group (from 11.02 ± 2.51 m/s to 9.61 ± 2.39 m/s and from 28.8 ± 10.3% to 26.2 ± 12.1%; p = 0.008 and p = 0.04, respectively). While augmentation index increased in the CHD group (28.0 ± 9.4 to 31.0 ± 10.7%, p = 0.02), pulse wave velocity did not change. Subendocardial viability ratio and ejection duration improved in the NHD group (from 135 ± 28 to 143 ± 25%, p = 0.01 and from 294 ± 34 ms to 281 ± 34 ms, p = 0.003, respectively), accompanied by regression of left ventricular mass index. In multiple stepwise linear regression analyses, NHD was associated with improvements in augmentation index, ejection duration and subendocardial viability ratio.ConclusionsThese data indicate that arterial stiffness is ameliorated by implementation of longer hemodialysis sessions.     

Idiopathic synchronous central giant cell granulomas involving both the maxilla and mandible: a case report

The central giant cell granuloma is a well-defined lesion of the jaws and reports of multiple lesions are very uncommon. The authors report the case of a patient with idiopathic synchronous multiple central giant cell granulomas involving both the maxilla and the mandible. Surgical curettage of the lesions was performed. At the end of the 24 months follow-up, no recurrence was detected.     

Interleukin‐2 gene polymorphism in Turkish patients with Behçet's disease and its association with ocular involvement

Behçet's disease (BD) is a chronic immune‐mediated systemic disease, characterized by oral and genital lesions and ocular inflammation. Several cytokine genes may play crucial roles in host susceptibility to BD, because the cytokine production capacity varies among individuals and depends on the cytokine gene polymorphisms. The association of the interleukin (IL)‐2 gene polymorphisms with the susceptibility to BD was investigated in this study. DNA samples were obtained from a Turkish population of 97 patients with BD and 76 healthy control subjects. Polymorphisms of IL‐2 gene at position ?330 and +166 were determined using the polymerase chain reaction with sequence‐specific primers. In the patients with BD, there was a significantly increased frequency of IL‐2 ?330 GT genotype. Interestingly, we demonstrated that the frequencies of IL‐2 ?330 GT and IL‐2 + 166 GG genotypes were increased in BD patients with ocular involvement, whilst IL‐2 ?330 TT genotype was significantly decreased. Also, analysis of allele frequency demonstrated that the presence of G allele at position +166 of IL‐2 seems to be a risk factor for ocular involvement. These results reveal that IL‐2 ?330 GT genotype may be a susceptibility factor for BD, whereas IL‐2 ?330 TT genotype seems to display a protective association with BD. Additionally, IL‐2 gene polymorphisms might be associated with ocular involvement in BD.     

Effect of catheter ablation on progression of paroxysmal atrial fibrillation

Ablation and Progression of Atrial Fibrillation. Objective: The objective was to determine the effect of radiofrequency catheter ablation (RFA) on progression of paroxysmal atrial fibrillation (AF). Background: Progression to persistent AF may occur in up to 50% of patients with paroxysmal AF receiving pharmacological therapy. Hypertension, age, prior transient ischemic event, chronic obstructive pulmonary disease, and heart failure (HATCH score) have been identified as independent risk factors for progression of AF. Methods: RFA was performed in 504 patients (mean age: 58 ± 10 years) to eliminate paroxysmal AF. A repeat RFA procedure was performed in 193 patients (38%). Clinical variables predictive of outcome and their relation to progression of AF after RFA were assessed using multivariate analysis. Results: At a mean follow‐up of 27 ± 12 months after RFA, 434/504 patients (86%) were in sinus rhythm; 49/504 patients (9.5%) continued to have paroxysmal AF; and 14 (3%) were in atrial flutter. Among the 504 patients, 7 (1.5%) progressed to persistent AF. In patients with recurrent AF after RFA, paroxysmal AF progressed to persistent AF in 7/56 (13%, P < 0.001). The progression rate of AF was 0.6% per year after RFA (P < 0.001 compared to 9% per year reported in pharmacologically treated patients). Age >75 years, duration of AF >10 years and diabetes were independent predictors of progression to persistent AF. The HATCH score was not significantly different between patients with paroxysmal AF who did and did not progress to persistent AF (0.7 ± 0.8 vs 1.0 ± 0.5, P = 0.3). Conclusions: Compared to a historical control group of pharmacologically treated patients with paroxysmal AF, RFA appears to reduce the rate of progression of paroxysmal AF to persistent AF. Age, duration of AF, and diabetes are independent risk factors for progression to persistent AF after RFA. (J Cardiovasc Electrophysiol, Vol. 23, pp. 9‐14, January 2012)