Conditional mouse models demonstrate oncogene-dependent differences in tumor maintenance and recurrence

Diversity in the pathophysiology of breast cancer frustrates therapeutic progress. We need to understand how mechanisms activated by specific combinations of oncogenes, tumor suppressors, and hormonal signaling pathways govern response to therapy and prognosis. A recent series of investigations conducted by Chodosh and colleagues offers new insights into the similarities and differences between specific oncogenic pathways. Expression of three oncogenes relevant to pathways activated in human breast cancers (c-myc, activated neu and Wnt1) were targeted to murine mammary epithelial cells using the same transgenic tetracycline-responsive conditional gene expression system. While the individual transgenic lines demonstrate similarly high rates of tumor penetrance, rates of oncogene-independent tumor maintenance and recurrence following initial regression are significantly different, and are modifiable by mutations in specific cooperating oncogenes or loss of tumor suppressor gene expression. The experiments make three notable contributions. First, they illustrate that rates of tumor regression and recurrence following initial regression are dependent upon the pathways activated by the initiating oncogene. The experiments also demonstrate that altered expression or mutation of specific cooperating oncogenes or tumor suppressor genes results in different rates of tumor regression and recurrence. Finally, they exemplify the power of conditional mouse models for elucidating how specific molecular mechanisms give rise to the complexity of human cancer.     

Fecal levels of short-chain fatty acids and bile acids as determinants of colonic mucosal cell proliferation in humans

We studied the correlation between fecal levels of short-chain fatty acids (SCFA), bile acids (BA), and colonic mucosal proliferation in humans on a free diet. Subjects [n = 43: 27 men and 16 women; 61 +/- 7 and 59 +/- 6 (SE) yr old, respectively] were outpatients who previously underwent resection of at least two sporadic colon polyps. Mucosal proliferation was determined by [3H]thymidine incorporation in vitro in three colorectal biopsies obtained without cathartics and was expressed as labeling index (LI). BA were analyzed in feces by mass spectrometry and SCFA by gas chromatography. We found that increasing levels of BA in feces did not correlate with higher LI. On the contrary, higher levels of SCFA were significantly associated with lower LI in the colonic mucosa (P for trend = 0.02). In conclusion, in humans on a free diet, intestinal proliferation seems to be regulated by the levels of SCFA in feces and not by BA. Because a lower intestinal proliferation is associated with a decreased colon cancer risk, treatments or diets that increase colonic levels of SCFA might be beneficial for colonic mucosa.     

Exudative idiopathic polypoidal choroidal vasculopathy and photodynamic therapy with verteporfin

PURPOSE: To report two cases of exudative idiopathic polypoidal choroidal vasculopathy treated by photodynamic therapy with verteporfin. DESIGN: Interventional case reports. METHODS: Two patients, a man aged 58 years and a woman aged 57 years, with recent visual impairment in the right eye (OD) (both eyes best-corrected visual acuity: 10/50 and Pelli-Robson contrast sensitivity 1.35 and 1.20) and angiographically proved subfoveal idiopathic polypoidal choroidal vasculopathy were treated with photodynamic therapy using verteporfin (Visudyne; Novartis SA, Rueil Malmaison, France). Functional and angiographic outcomes were assessed 6 weeks and 3, 6, and 12 months after treatment. RESULTS: In Patient 1, 3 months after treatment, best-corrected visual acuity and contrast sensitivity improved (10/16 and 1.50) and then remained stable throughout the 12 months after treatment. In Patient 2, 6 weeks after treatment, vision and contrast sensitivity were 10/20 and 1.35; and at 3 months, were improved and stabilized at 10/12.5 and 1.50. Angiographically, photodynamic therapy with verteporfin was associated with nonperfusion and occlusion of the exudative polypoidal dilations. No acute recurrence was noted during the follow-up period. CONCLUSION: In subfoveal exudative idiopathic polypoidal choroidal vasculopathy, photodynamic therapy with verteporfin may be associated with beneficial functional results.     

Do Diet and Lifestyles Play a Role in the Pathogenesis of NMSCs?

Background and Aims: Literature highlights the role of risk factors like age, body mass index (BMI), tobacco smoking, alcohol intake and diet in the pathogenesis of several cancer types but little is known for non-melanoma skin cancers (NMSC). The aim of this epidemiological study was to evaluate the correlation between modifiable risk factors (BMI, metabolic panel, diet, lifestyle, medical history) and not modifiable risk factors (gender, age) and NMSC development. Methods: From February 2018 to September 2019, 162 patients affected by NMSC were compared to a group of 167 controls. A univariate and multivariate analysis was conducted to elaborate the data collected through face-to-face interviews. Results: While our evidence did not always reach statistical significance, NMSC study group patients exhibited high rates of analyzed risk factors (male gender aging over 55 years, high BMI, reduced physical activity) compared to the control group. Conclusions: Our study indicates that practicing more than 30 min of physical activity daily could be a protective factor against the NMSC onset. Other risk factors were not correlated with NMSC, but more evidence is needed to establish a possible link.     

TRAP1: a viable therapeutic target for future cancer treatments?

Introduction: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors.

Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria.

Expert opinion: TRAP1 targeting may represent a promising strategy for cancer therapy, based on the increasing and compelling evidence supporting TRAP1 involvement in human carcinogenesis. However, considering the complexity of TRAP1 biology, future strategies of drug discovery need to improve selectivity and specificity toward TRAP1 respect to other HSP90 paralogs. The characterization of specific human malignancies suitable for TRAP1 targeting is also mandatory.     

l-DOPA treatment of parkinsonian rats changes the expression of Src,Lyn and PKC kinases

The dopamine (DA) precursor l-DOPA remains the most common treatment for Parkinson's disease (PD). However, long-term treatment with l-DOPA induces dyskinesia and motor disabilities in PD patients, indicating that this pharmacological agent is unable to fully compensate for the effects of DA denervation when used chronically. In this study, we examined the effect 6-hydroxydopamine (6-OHDA)-induced DA denervation of the striatum followed by either acute or chronic treatment with l-DOPA on gene expression of critical regulators of glutamate synaptic transmission. We found that administration of l-DOPA in rats with unilateral DA denervation resulted in a progressive increase of contraversive circling behavior and modulated the expression of Src, Lyn and PKC kinases. In particular, acute (3 days) and chronic (21 days) l-DOPA treatment were differentially able to rescue the effects of DA lesion, since only the acute treatment with l-DOPA corrected the decrease in Src, Lyn and PKC kinase expression induced by 6-OHDA lesion. Also, the reduced phosphorylation level of NR1 receptor subunit induced by 6-OHDA was only partially reversed by chronic l-DOPA treatment.     

Clinical outcomes and predictors of maternal and fetal complications in pregnancies of patients with systemic lupus erythematosus

Introduction: Systemic Lupus Erythematosus (SLE) mostly affects women during their childbearing years. Fertility is preserved in SLE patients, but pregnancy is often characterized by a high number of maternal and fetal complications. Adverse pregnancy outcomes (APO) have been widely studied over the last decades and several investigators have focused on the potential clinical and serological predictors of maternal and fetal complications.

Areas covered: In this review, we analyzed maternal and fetal complications in SLE patients and predictors of APO. Active disease in the 6 months before conception, lupus nephritis, anti-phospholipid (aPL), anti-SSA/Ro and/or anti-SSB/La antibodies have been identified as the most consistent predictors of maternal and fetal complications to date. However, molecular mechanisms and underlying immunological pathways involved in APO still remain elusive.

Expert opinion: Difficulties in assessing prevalence and predictors of APO in SLE patients are due to lack of uniformity in the definitions and methods used in the different studies. In addition, some maternal and fetal complications are difficult to diagnose and to differentiate from each other. Preconception counseling is paramount to prevent APO, and it should consider four main factors: disease activity/lupus nephritis, safety of drugs, aPL, anti-SSA/Ro, and/or anti-SSB/La antibodies.