Dichloroacetate,a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment

Reprogramming of metabolism is a well-established property of cancer cells that is receiving growing attention as potential therapeutic target. Oral squamous cell carcinomas (OSCC) are aggressive and drugs-resistant human tumours displaying wide metabolic heterogeneity depending on their malignant genotype and stage of development. Dichloroacetate (DCA) is a specific inhibitor of the PDH-regulator PDK proved to foster mitochondrial oxidation of pyruvate. In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15. Characterization of the three cell lines unveiled for HSC-2 and HSC-3 a glycolysis-reliant metabolism whereas PE15 accomplished an efficient mitochondrial oxidative phosphorylation. DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro-apoptotic/cytostatic effect on HSC-2 and HSC-3. This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species. The data here presented indicate that the therapeutic efficacy of DCA may depend on the specific metabolic profile adopted by the cancer cells with those exhibiting a deficient mitochondrial oxidative phosphorylation resulting more sensitive to the drug treatment.     

GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo

We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC.     

Triple negative breast cancer: looking for the missing link between biology and treatments

The so called “Triple Negative Breast Cancer” (TNBC) represents approximately 15-20% of breast cancers. This acronym simply means that the tumour does not express oestrogen receptor (ER) and progesterone receptor (PR) and does not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene. Despite this unambiguous definition, TNBCs are an heterogeneous group of tumours with just one common clinical feature: a distinctly aggressive nature with higher rates of relapse and shorter overall survival in the metastatic setting compared with other subtypes of breast cancer. Because of the absence of well-defined molecular targets, cytotoxic chemotherapy is currently the only treatment option for TNBC.In the last decades, the use of more aggressive chemotherapy has produced a clear improvement of the prognosis in women with TNBC, but this approach results in an unacceptable deterioration in the quality of life, also if some support therapies try to relieve patients from distress. In addition, there is the general belief that it is impossible to further improve the prognosis of TNBC patients with chemotherapy alone. In view of that, there is a feverish search for new “clever drugs” able both to rescue chemo-resistant, and to reduce the burden of chemotherapy in chemo-responsive TNBC patients.A major obstacle to identifying actionable targets in TNBC is the vast disease heterogeneity both inter-tumour and intra-tumour and years of study have failed to demonstrate a single unifying alteration that is targetable in TNBC. TNBC is considered the subtype that best benefits from the neoadjuvant model, since the strong correlation between pathological Complete Response and long-term Disease-Free-Survival in these patients.In this review, we discuss the recent discoveries that have furthered our understanding of TNBC, with a focus on the subtyping of TNBC. We also explore the implications of these discoveries for future treatments and highlight the need for a completely different type of clinical trials.     

Periodontal response to orthodontic tooth movement in diabetes‐induced rats with or without periodontal disease

1 Background

Systemic conditions can influence orthodontic tooth movement. This study evaluates histologic periodontal responses to orthodontic tooth movement in diabetes‐induced rats with or without periodontal disease.

2 Methods

Forty Wistar rats were divided according their systemic condition (SC) into diabetic (D) and non‐diabetic (ND) groups. Each group was subdivided into control (C), orthodontic tooth movement (OM), ligature‐induced periodontitis (P) and ligature‐induced periodontitis with orthodontic movement (P+OM) groups. Diabetes mellitus (DM) was induced with alloxan monohydrate, and after 30 days, the P group received a cotton ligature around their first lower molar crown. An orthodontic device was placed in OM and P+OM groups for 7 days, and the animals were then euthanized.

3 Results

Differences in OM between D and ND groups were not significant (6.87± 3.55 mm and 6.81 ± 3.28 mm, respectively), but intragroup analysis revealed statistically significant differences between the P+OM groups for both SCs. Bone loss was greater in the D group (0.16 ± 0.07 mm²) than in the ND group (0.10 ± 0.03 mm²). In intragroup analysis of the D condition, the P+OM group differed statistically from the other groups, while in the ND condition, the P+OM group was different from the C and OM groups. There was a statistically significant difference in bone density between D and ND conditions (18.03 ± 8.09% and 22.53 ± 7.72%) in the C, P, and P+OM groups.

4 Conclusion

DM has deleterious effects on bone density and bone loss in the furcation region. These effects are maximized when associated with ligature‐induced periodontitis with orthodontic movement.     

Radiographic patterns of multiple myeloma in the jawbones of patients treated with intravenous bisphosphonates

Background

The purpose of this study was to evaluate whether intravenous (IV) bisphosphonate (BP) therapy can change the radiographic patterns of multiple myeloma (MM) in the jawbones.

Ultrasound characteristics of gouty tophi in the olecranon bursa and evaluation of their reproducibility

Objectives

To describe the ultrasound characteristics of gouty tophi in the olecranon bursa and to evaluate their reproducibility.

Methods

A prospective study of the ultrasound features of 35 sites of tophi nodulations in the elbows of 31 men (mean 54.6 years). The findings were evaluated dynamically following pre-established standards. The static images were evaluated by another radiologist and were reviewed by the first examiner.

Results

The most frequent characteristics of tophi are: hyperechogenicity (91.7%), poorly defined contours (88.6%), multiple grouped nodules (85.6%) and heterogeneity (68.6%). Intra-observer agreement is almost perfect for echogenicity (K = 1.0), moderate for the involvement of the olecranon bursa (K = 0.47) and fair for other characteristics. Inter-observer agreement is substantial for the echogenicity (K = 0.65), fair for the echotexture (K = 0.27) and the presence of a perilesional hypoechoic halo (K = 0.34) and slight for other characteristics.

Conclusions

The most frequent characteristic of tophi is hyperechogenicity. The intra-observer and inter-observer concordance for echogenicity are almost perfect and substantial, respectively. Knowledge of characteristics of the tophi in the elbow and their intra and inter-observer reproducibility may assist in establishing parameters for monitoring treatment and setting up criteria for differential diagnosis of processes involving the olecraneon bursa.