Role of definitive chemoradiotherapy using docetaxel and 5-fluorouracil in patients with unresectable locally advanced esophageal squamous cell carcinoma: a phase II study.

Definitive chemoradiotherapy (CRT) with docetaxel (DOC) and 5-fluorouracil (5-FU) is a unique regimen for esophageal cancer. In this prospective phase II study, antitumor effect and safety of CRT using DOC and 5-FU for inoperable locally advanced esophageal cancer were evaluated. DOC 7.5 mg/m2 was infused on days 1, 8, 22, and 29. 5-FU 250 mg/m2 /day was infused continuously on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-45. Radiotherapy was given to 66 Gy in 33 fractions. Eleven patients with thoracic and five with cervical esophageal cancer were eligible. All patients had esophageal squamous cell carcinoma (ESCC). The response rate was 94%, with complete response in five patients (31%) and partial response in 10 (63%). Hematologic toxicity was mild; only one patient (6%) had Grade 1 leukopenia. Nonhematologic Grade 3 or higher adverse events were esophagitis (31%), anorexia (6%), and esophago-bronchial fistula (6%). No treatment-related deaths occurred. The median time to progression was 20 months and overall 3-year and 5-year survival were 44% and 31%, respectively. Definitive CRT using DOC and 5-FU could be performed safely, and it demonstrated a favorable antitumor effect for ESCC. This regimen might be indicated in patients in whom it is desirable to avoid myelosuppression and progression of renal impairment.

Lateral prefrontal cortex is organized into parallel dorsal and ventral streams along the rostro-caudal axis.

Anatomical connectivity differences between the dorsal and ventral lateral prefrontal cortex (PFC) of the non-human primate strongly suggests that these regions support different functions. However, after years of study, it remains unclear whether these regions are functionally distinct. In contrast, there has been a groundswell of recent studies providing evidence for a rostro-caudal functional organization, along the lateral as well as dorsomedial frontal cortex. Thus, it is not known whether dorsal and ventral regions of lateral PFC form distinct functional networks and how to reconcile any dorso-ventral organization with the medio-lateral and rostro-caudal axes. Here, we used resting-state connectivity data to identify parallel dorsolateral and ventrolateral streams of intrinsic connectivity with the dorsomedial frontal cortex. Moreover, we show that this connectivity follows a rostro-caudal gradient. Our results provide evidence for a novel framework for the intrinsic organization of the frontal cortex that incorporates connections between medio-lateral, dorso-ventral, and rostro-caudal axes.

Double dissociation of two cognitive control networks in patients with focal brain lesions.

Neuroimaging studies of cognitive control have identified two distinct networks with dissociable resting state connectivity patterns. This study, in patients with heterogeneous damage to these networks, demonstrates network independence through a double dissociation of lesion location on two different measures of network integrity: functional correlations among network nodes and within-node graph theory network properties. The degree of network damage correlates with a decrease in functional connectivity within that network while sparing the nonlesioned network. Graph theory properties of intact nodes within the damaged network show evidence of dysfunction compared with the undamaged network. The effect of anatomical damage thus extends beyond the lesioned area, but remains within the bounds of the existing network connections. Together this evidence suggests that networks defined by their role in cognitive control processes exhibit independence in resting data.

A novel metalloprotease/disintegrin-like gene at 17q21.3 is somatically rearranged in two primary breast cancers.

From chromosomal region 17q21.3, where a tumour suppressor gene(s) for breast and ovarian cancers is thought to be present, we have isolated a novel gene from a cosmid clone that revealed somatic rearrangements in two breast cancers. The gene (MDC) encodes a 524-amino acid metalloprotease-like, disintegrin-like and cysteine-rich protein with sequence similarity to members of the snake-venom metalloprotease/disintegrin family and guinea-pig sperm-surface protein PH-30. These proteins have been implicated in cell-cell or cell-extracellular matrix interactions. Rearrangements in both tumours involve multiple exons and disrupt the coding region of the new MDC.

Focal brain lesions to critical locations cause widespread disruption of the modular organization of the brain.

Although it is generally assumed that brain damage predominantly affects only the function of the damaged region, here we show that focal damage to critical locations causes disruption of network organization throughout the brain. Using resting state fMRI, we assessed whole-brain network structure in patients with focal brain lesions. Only damage to those brain regions important for communication between subnetworks (e.g., "connectors")--but not to those brain regions important for communication within sub-networks (e.g., "hubs")--led to decreases in modularity, a measure of the integrity of network organization. Critically, this network dysfunction extended into the structurally intact hemisphere. Thus, focal brain damage can have a widespread, nonlocal impact on brain network organization when there is damage to regions important for the communication between networks. These findings fundamentally revise our understanding of the remote effects of focal brain damage and may explain numerous puzzling cases of functional deficits that are observed following brain injury.

Characterization of Residual Facial Dermatitis during Dupilumab Therapy: A Retrospective Chart Review to Delineate the Potential Role of Expanded Series Patch Testing.

OBJECTIVE: We sought to determine the incidence of RFDD in patients receiving dupilumab and the rate of resolution of RFDD after expanded series patch testing (ESPT) and allergen avoidance. METHODS: This is a retrospective chart review of 80 patients with atopic dermatitis who were evaluated for RFDD after treatment with dupilumab. Expanded series patch testing findings and response to allergen avoidance were assessed in the subset of patients with RFDD who subsequently underwent ESPT while continuing to receive dupilumab. RESULTS: Forty-nine patients (61.3%) experienced facial dermatitis before initiating dupilumab. Thirty-five patients (43.8%) experienced RFDD after starting dupilumab. Of the 14 patients with RFDD who received ESPT, 92.9% had 1 or more relevant positive patch test results, with 50% of such patients being mostly to completely clear of facial dermatitis after allergen avoidance. Importantly, 50.6% of the positive reactions to allergens were not included on the North American Contact Dermatitis Group Core 80. CONCLUSIONS: Many patients with RFDD benefit from patch testing and subsequent allergen avoidance. Expanded series patch testing should be offered to patients who experience RFDD after beginning dupilumab therapy to ensure that such patients have eliminated any exogenous component of their dermatitis, such as concomitant allergic contact dermatitis.

Ethanol-induced locomotor sensitization: Neuronal activation in the nucleus accumbens and medial prefrontal cortex.

Ethanol consumption may promote neuroplasticity and alterations in synapses, resulting in modifications in neuronal activity. Here, we treated male Swiss mice with ethanol (2.2 g/kg) or saline once per day for 21 consecutive days. Nine days after the last ethanol administration, they received a challenge injection of ethanol or saline, and we assessed locomotor activity. After the behavioral analysis, we evaluated neuronal activation in the medial Prefrontal Cortex (Cingulate, Prelimbic, and Infralimbic) and the Nucleus Accumbens (Shell and Core) using Fos/DAB immunohistochemistry. In another group of animals, we performed the quantitative analysis of the ARC and PSD-95 protein levels by Western blotting in the medial prefrontal cortex and nucleus accumbens brain areas. Repeated ethanol administration produced locomotor sensitization, accompanied by an increase in the nucleus accumbens shell's activation but not core. Furthermore, the ethanol pretreatment reduced ARC expression in the nucleus accumbens and medial prefrontal cortex. Our results suggest the participation of the nucleus accumbens shell in ethanol behavioral sensitization and add new pieces of evidence that neuroplasticity in synapses may contribute to the mechanism underlying this behavior.

Colic Surgery in Horses: A Retrospective Study Into Short- and Long-Term Survival Rate, Complications and Rehabilitation toward Sporting Activity.

Colic surgery in horses impacts both short-term well-being of horses due to possible surgical and anesthetic complications and also long-term return to a sporting career. In this retrospective study, survival and complication rates, as well as functional outcome and behavioral problems in horses that underwent colic surgery were studied. Data from 283 horses that underwent colic surgery at a veterinary teaching hospital were analyzed. Furthermore, owners were contacted and requested to fill out a questionnaire concerning the first year of rehabilitation. Of 283 horses that underwent colic surgery, 167 (59%) were discharged home. After discharge from hospital, 34 horses (12%) were lost to follow-up. Of the remaining 133 horses, 128 were still alive after 1 year (96.2%), while 5 horses were euthanized due to recurrent colic. Of the horses that did not survive the hospitalization period 73 horses (25.8%) were euthanized intraoperatively and 36 horses (12.7%) during intensive care unit (ICU) stay. Survival of horses entering the ICU up to discharge from hospital was 79.5%. During rehabilitation, 49 horses (59.8%) that returned home experienced one or more recurrences of colic. Fifty-two horses (63.4%) that returned home reached at least preoperative level of performance. Altered behavior and gait-related problems during specific elements of riding (for instance during collecting, lateral bending, etc.) were reported in up to 46.2% of horses. Improving veterinary aftercare in collaboration with other disciplines (e.g., physiotherapy and saddle fitting) during rehabilitation could be a means to further improve athletic performance and welfare after recovery from colic surgery.

A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity.

Anaplastic thyroid cancer (ATC) is one of the most lethal of all human tumors, but cytogenetic information concerning ATC is extremely limited. Using our in-house array-based comparative genomic hybridization and 14 ATC cell lines with further fluorescence in situ hybridization analysis, we demonstrated amplification of the DUSP26 gene, known by another report as MAP kinase phosphatase-8. DUSP26 was overexpressed in ATC cell lines and primary ATC tumor samples. When overexpressed, either exogenously or endogenously, DUSP26 promoted growth of the ATC cells. DUSP26 encodes a protein containing a dual-specificity phosphatase domain that can dephosphorylate itself. DUSP26 effectively dephosphorylates p38 and has a little effect on extracellular signal-regulated kinase in ATC cells. DUSP26 protein formed a physical complex with p38, and promoted survival of ATC cells by inhibiting p38-mediated apoptosis. Our findings suggest that DUSP26 may act as an oncogene in ATC, and might be a useful diagnostic marker and therapeutic target of this disease.

Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation.

Familial lipoprotein lipase (LPL) deficiency is a rare genetic disorder accompanied by well-characterized manifestations. The phenotypic expression of heterozygous LPL deficiency has not been so clearly defined. We studied the pedigree of a proband known to be homozygous for a mutation resulting in nonfunctional LPL. Hybridization of DNA from 126 members with allele-specific probes detected 29 carriers of the mutant allele. Adipose tissue LPL activity, measured previously, was reduced by 50% in carriers, but did not reliably distinguish them from noncarriers. Carriers were prone to the expression of a form of familial hypertriglyceridemia characterized by increased plasma triglyceride, VLDL cholesterol and apolipoprotein B, and decreased LDL and HDL cholesterol concentrations. These manifestations were age modulated, with conspicuous differences between carriers and noncarriers observed only after age 40. Several noncarriers exhibited similar lipid abnormalities, but without the inverse relationship between VLDL cholesterol and LDL cholesterol noted among carriers. In addition to age and carrier status, the potentially reversible conditions, obesity, hyperinsulinemia and lipid-raising drug use were contributory. Thus heterozygous lipoprotein lipase deficiency, together with age-related influences, may account for a form of familial hypertriglyceridemia.

Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy.

Bcl-2 is an oncoprotein that plays a critical role in inhibiting apoptotic cell death in the mitochondria-dependent pathway in cancer chemotherapy. As a strategy for blocking Bcl-2 for enhancement of the chemotherapeutic effect, antisense Bcl-2 (AS Bcl-2; G3139, oblimersen sodium, Genasense) has shown promise, and there are several ongoing clinical studies with hematological malignancies as well as solid tumors. Although several preclinical and clinical studies have shown the therapeutic efficacy of Bcl-2 in combination with an anticancer drug as a chemosensitizer, in clinical trials the downregulation of Bcl-2 has not been observed with a high frequency in tumor cells. Nevertheless, previous studies showed nonantisense effects such as production of reactive oxygen species and immunostimulatory action through cytosine-phosphate-guanosine-motif in the antisense oligodeoxynucleotides. Further, Bcl-2 is able to inhibit Beclin 1-dependent autophagic cell death, which is a nonapoptotic cell death. The current status and future directions of AS Bcl-2 and the potential mechanisms for multiple roles that Bcl-2 has in cancer therapy are reviewed.

A polymorphism of the aldehyde dehydrogenase 2 gene is a risk factor for multiple lacunar infarcts in Japanese men: the Takahata Study.

The objective of the present study was to examine the association between a polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene and lacunar infarcts of the brain. We conducted a population-based, cross-sectional study on residents from two age groups (61- and 72-year olds). A total of 376 subjects participated in the study, which included brain magnetic resonance image and genetic analysis of the ALDH2 gene. Of the 61- and 72-year-old subjects, 46.4% and 64.3%, respectively, had one or more lacunar infarcts. The average number of infarcts also increased from 2.0 to 2.8 in men and from 2.3 to 3.5 in women. No significant association between the ALDH2 genotype and the presence of lacunar infarction (> or =1) was found. However, in subjects with lacunar infarction, the genotype of ALDH2 *1/*1 was associated with a larger number of the lesion ['single' versus 'multiple' odds ratio (OR) 3.73, 95%CI: 1.43-9.74] in men. The OR was comparable even after adjusting for alcohol consumption, tobacco habits, age, hypertension, hypercholesterolemia, and diabetes mellitus (DM) (OR 3.88; 95% CI: 1.10-13.66). In women, there was no significant association between the ALDH2 genotypes and lacunar infarcts. The present study revealed that the ALDH2 *1/*1 genotype was significantly associated with the prevalence of multiple lacunar infarcts in Japanese men.

Copy number loss in the region of the ASPN gene in patients with acetabular dysplasia: ASPN CNV in acetabular dysplasia.

OBJECTIVES: We have previously investigated an association between the genome copy number variation (CNV) and acetabular dysplasia (AD). Hip osteoarthritis is associated with a genetic polymorphism in the aspartic acid repeat in the N-terminal region of the asporin (ASPN) gene; therefore, the present study aimed to investigate whether the CNV of ASPN is involved in the pathogenesis of AD. METHODS: Acetabular coverage of all subjects was evaluated using radiological findings (Sharp angle, centre-edge (CE) angle, acetabular roof obliquity (ARO) angle, and minimum joint space width). Genomic DNA was extracted from peripheral blood leukocytes. Agilent's region-targeted high-density oligonucleotide tiling microarray was used to analyse 64 female AD patients and 32 female control subjects. All statistical analyses were performed using EZR software (Fisher's exact probability test, Pearson's correlation test, and Student's t-test). RESULTS: CNV analysis of the ASPN gene revealed a copy number loss in significantly more AD patients (9/64) than control subjects (0/32; p = 0.0212). This loss occurred within a 60 kb region on 9q22.31, which harbours the gene for ASPN. The mean radiological parameters of these AD patients were significantly worse than those of the other subjects (Sharp angle, p = 0.0056; CE angle, p = 0.0076; ARO angle, p = 0.0065), and all nine patients required operative therapy such as total hip arthroplasty or pelvic osteotomy. Moreover, six of these nine patients had a history of operative or conservative therapy for developmental dysplasia of the hip. CONCLUSIONS: Copy number loss within the region harbouring the ASPN gene on 9q22.31 is associated with severe AD. A copy number loss in the ASPN gene region may play a role in the aetiology of severe AD.Cite this article: T. Sekimoto, M. Ishii, M. Emi, S. Kurogi, T. Funamoto, Y. Yonezawa, T. Tajima, T. Sakamoto, H. Hamada, E. Chosa. Copy number loss in the region of the ASPN gene in patients with acetabular dysplasia: ASPN CNV in acetabular dysplasia. Bone Joint Res 2017;6:439-445. DOI: 10.1302/2046-3758.67.BJR-2016-0094.R1.

The role of apoptotic or nonapoptotic cell death in determining cellular response to anticancer treatment.

AIMS: Apoptosis, an early response cell death, is a useful marker for predicting tumour response after anticancer treatment; however, late-response cell death or nonapoptotic cell death, autophagy, can also be observed. This article reviews a rational model for predicting tumour response by assessing the influence of nonapoptotic cell death, and thereby developing a more efficient strategy for enhancing the therapeutic effect of anticancer treatment. METHOD: Literature search of clinical and experimental studies on "cell death and cancer" using established databases, including PUBMED. FINDINGS: Although induction of apoptosis may not contribute to overall tumour response, nonapoptotic cell death such as autophagy, which may be triggered by apoptosis, still occurs. Anticancer treatment-induced apoptosis is regulated by the balance of proapoptoic and antiapoptoic proteins through mitochondria, and resistance to apoptosis is mediated by Bcl-2-dependent and Akt-dependent pathways. Bcl-2 partially inhibits nonapoptotic cell death as well as apoptosis, whereas Akt inhibits both apoptotic and nonapoptotic cell death through several target proteins. CONCLUSIONS: Drug sensitivity is likely correlated with the accumulation of apoptotic and nonapoptotic cell deaths, which may influence overall tumour response in anticancer treatment. The ability to predict overall tumour response from the modulation of several important cell death-related proteins may result in a more efficient strategy for improving the therapeutic effect.

Frequent multiplication of the long arm of chromosome 8 in hepatocellular carcinoma.

Frequent allelic losses at loci on several chromosomes have been detected in human hepatocellular carcinomas, but other types of chromosomal abnormalities have not been characterized well. Using eight polymorphic DNA markers on chromosome 8, we examined 120 primary hepatocellular carcinomas for abnormalities in the copy number of these loci in tumor cells. A 2- to 6-fold increase in intensities of bands representing single alleles was observed in 32 of the 78 tumors that were informative for one or more of the markers, indicating an increase in copy number ("multiplication") of alleles on 8q. The regions that multiplied varied from almost the entire long arm to a distal segment of chromosome 8, but a terminal region distal to 8q24.11 was multiplied in all 32 cases. Similar multiplications on 8q were detected in nine of 56 colorectal carcinomas that were informative for one or more of the markers. Our study demonstrated that polymorphic DNA markers can be used to detect numerical abnormalities of chromosomal material in solid tumors in which cytogenetic analysis is technically difficult.

Evidence for the presence of two tumor suppressor genes on chromosome 8p for colorectal carcinoma.

We have examined loss of heterozygosity on the short arm of chromosome 8 in 133 colorectal carcinomas, using 20 restriction fragment length polymorphism markers. Loss of heterozygosity was observed in 58 (44%) of 131 tumors that were informative with at least one locus. Among these 58, 32 revealed a partial or interstitial deletion of chromosome 8p. Detailed deletion mapping of chromosome 8p in these tumors identified two distinct, commonly deleted regions. One was located between markers C18-266 and pSVL-LPL at 8p23.2-8p22, and the other between CI8-319 and CI8-494 at 8p21.3-8p11.22. The genetic lengths of these two intervals were estimated to be 28 and 18 cM, respectively. The results suggest that at least two tumor suppressor genes associated with colorectal carcinomas are present on chromosome 8p. Correlation of loss of heterozygosity on 8p to the clinicopathological stage was also detected, suggesting that inactivation of a tumor suppressor gene(s) on 8p plays a role in progression of colorectal carcinomas.

Expression of alpha-amylase in human lung cancers.

Thirty-three human lung tumors were studied for the expression of alpha-amylase by immunohistochemical and Northern blot analyses. Twenty of them were adenocarcinomas, among which 17 proved to be adequate for mRNA analyses and were, except for two, amylase mRNA producers. Seven were squamous cell carcinomas, none of which produced amylase. The remaining six consisted of two undifferentiated small cell carcinomas, and one each of undifferentiated large cell carcinoma, carcinoid tumor, mucoepidermoid carcinoma, and metastatic lung cancer; the mucoepidermoid carcinoma proved to be an amylase producer. These observations strongly suggest that among lung cancers, the production of alpha-amylase is a property commonly associated with adenocarcinomas and can be used for distinguishing cell types. Histogenesis and carcinogenesis in lung cells are discussed in connection with the cells that produce amylase.