Phenotype and cell proliferation activity of duct-like structures in human sublingual glands: a histological and immunohistochemical study

There are several age-related microscopic changes in the salivary glands, including the increase in the number of duct-like structures (DLS). However, the true origin and the phenotype of the DLS are not known.

Objective

To evaluate the phenotype and the cell proliferation index of the DLS of human sublingual glands.

Material and Methods

Sixty sublingual glands obtained from human cadavers were divided into two groups - 0-30 and 61-90 years old. The phenotype was estimated by immunostaining for cytokeratin 19 (CK 19) and the S-100 protein as well as by the presence of mucin and glycogen. The cell proliferation index was determined by the Ki-67 antibody. The histochemical techniques used periodic acid-Schiff (PAS) and Alcian Blue. In each captured microscopic field, the DLS were counted to establish a percentage for the staining profile. The statistical analysis was accomplished using Student’s t-test, the Mann-Whitney test and Pearson’s correlation coefficient (p<0.05).

Results

Comparing both groups, only CK 19 showed a statistically significant difference (p=0.033), with the strongest expression in the elderly group. There was no significant difference between PAS and Alcian Blue (p=0.270). In both groups, the immunostaining for CK 19 was stronger than that for S-100 (p=0.004;p<0.001), but there was no correlation between the two immunomarkers (ρ=-0.163; p=0.315). There was no immunostaining for Ki-67.

Conclusions

DLS demonstrate a ductal phenotypic profile and do not present cell proliferation activity. DLS may represent a regressive process arising from acini or represent the result of metaplasia.     

The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors

CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.     

Three differentiation states risk-stratify bladder cancer into distinct subtypes

Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.     

Psammomatoid juvenile ossifying fibroma: an analysis of 2 cases affecting the mandible with review of the literature

Juvenile ossifying fibroma (JOF) is a rare fibro-osseous neoplasm, defined as a variant of the ossifying fibroma that arises within the craniofacial bones. Two subgroups, juvenile psammomatoid ossifying fibroma (PsJOF) and juvenile trabecular ossifying fibroma, have been delineated by their histology. PsJOF occurs predominantly in the sinonasal and orbital bones. This work reports on 2 cases of extensive PsJOF in the body of the right mandible as well as reviews the literature regarding the radiographic and histologic features, treatment, and prognosis of PsJOF of the jaws.     

Suggestive evidence for association between L‐type voltage‐gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family‐based association study

Objectives: Through recent genome‐wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage‐dependent, L‐type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European‐American cohorts. We performed a family‐based association study to determine whether CACNA1C is associated with BP in the Latino population. Methods: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single‐nucleotide polymorphisms (SNPs) that spanned a 602.9‐kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family‐Based Association Test (version 2.0.3) and Haploview (version 4.2) software. Results: An eight‐locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). Conclusions: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.     

Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes**

In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selectivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and orthosteric binding sites on dopamine receptors for the treatment of Parkinson’s disease, and on muscarinic receptors for Alzheimer’s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopamine receptor holds promise as a relevant therapeutic strategy for Parkinson’s disease. Regarding the treatment of Alzheimer’s disease, the design of dualsteric ligands for mono-oligomeric muscarinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.     

Resultados de la esofagectomía por cáncer tras la creación de un Comité de Tumores Esofagogástricos

Introduction

Treatment of oesophageal cancer with curative intent requires a multidisciplinary approach. Neoadjuvant therapy, the radicality of resection and extension of lymphadenectomy have been associated with increased operative morbidity and mortality. The aim of this study was to assess the results of surgical treatment of oesophageal cancer since the presence of an interdisciplinary esophagogastric tumour board.

Methods

Patients with cancer of the oesophagus and oesophagogastric junction who underwent oesophagectomy between January 2005 and March 2012 were included in this retrospective study. Data concerning type of resection, postoperative complications, mortality and survival were analysed.

Results

Of the 392 patients with a diagnosis of oesophageal cancer over the study period, 100 underwent oesophagectomy. Seventy-four patients received neoadjuvant treatment. Eighty-two patients underwent transthoracic resection while a transhiatal was used in 10 patients. Colon interposition was required in 8 cases. An R0 resection was achieved in 98 patients. Anastomotic leaks developed in 15 patients, 9 were intrathoracic and 6 were cervical. Postoperative morbidity occurred in 42% of patients, and intra-hospital and 90-day mortality was 2%. Median length of hospital stay was 16 days. The respective actuarial survival at 1 and 5 years were 82% and 56%.

Conclusions

Surgical treatment with curative intention for oesophageal cancer is only possible in a quarter of patients diagnosed. The high morbidity rate was mainly due to intrathoracic complications.     

Significant sleep disturbances in euthymic bipolar patients

Objective

A growing amount of data suggests that sleep dysfunction is frequently observed in bipolar disorder (BD) patients even when they do not fulfill the criteria for major mood episodes. Thus, we performed a case–control study assessing sleep status in a group of euthymic BD patients and a group of health controls.

Methods

A total of 209 subjects (104 health controls and 105 BD patients) were enrolled in the study. The Pittsburgh Sleep Quality Index (PSQI) was used for sleep assessment. Inclusion criteria for the BD group were a diagnosis of BD, following DSM-IV-TR criteria, according to the MINI-plus structured clinical interview. Euthymia was established as a score lower than 7 both in the Hamilton Depression Rating Scale (HDRS) and in the Young Mania Rating Scale (YMRS). Health controls were also interviewed using the MINI-plus and included in this study if they were free of any current or past DSM-IV-TR axis I psychiatric disorder as well the actual use of psychopharmacological medications.

Results

While 21.2 % of the control group displayed poor sleep quality according to the global PSQI-BR score, 82.9 % of the euthymic BD patients had poor sleep quality (p = 0.000). PSQI sleep duration subcomponent showed comparable results in the two groups (p = 0.535), even though BD patients had significant disruptions in sleep latency (p = 0.000) and sleep efficiency (p = 0.000) subcomponents.

Conclusion

We were able to show that BD patients, even in euthymic phase, exhibit a significantly worse sleep quality as compared with health controls as assessed by PSQI total score and five of its seven subcomponents.