Recovery from chronic depression and structural change: 5-year outcomes after psychoanalytic and cognitive-behavioural long-term treatments (LAC depression study).

OBJECTIVE: Psychotherapy of chronic depression has remained a challenge due to limited prognosis and high rates of recurrence. We present 5-year outcome data from a multicentre trial comparing psychoanalytic (PAT) and cognitive-behavioural (CBT) long-term treatments with randomized and preferred allocations analysing symptom (N = 227) and structural change (N = 134) trajectories. METHOD: Self- and blinded expert ratings of depression symptoms were performed at yearly intervals using the Beck Depression Inventory-II (BDI-II) and Quick Inventory of Depressive Symptoms (QIDS-C). Blinded expert ratings of Operationalized Psychodynamic Diagnosis (OPD) and the Heidelberg Restructuring Scale (HRS) at baseline, 1, 3, and 5 years assessed structural change in a subsample. RESULTS: Lasting and comparable symptom changes were achieved by PAT and CBT. However, compared to CBT, PAT was more successful in restructuring, a major goal of long-term psychodynamic treatments with high frequency and duration. LIMITATIONS: Due to practical reasons, the time criterion for chronic depression of an acute phase had to be defined for over 1 year in the present study, which does not correspond to the DSM-5 criterion of 2 years. Therapy duration and session frequency were not incorporated into the statistical models. CONCLUSION: Long-term psychotherapy helps patients with a yearlong history of depression and often multiple unsuccessful treatment attempts to achieve lasting symptom changes. Future follow-up will clarify whether restructuring promotes further sustainable improvements.

Discovery of a new molecule inducing melanoma cell death: dual AMPK/MELK targeting for novel melanoma therapies.

In the search of biguanide-derived molecules against melanoma, we have discovered and developed a series of bioactive products and identified the promising new compound CRO15. This molecule exerted anti-melanoma effects on cells lines and cells isolated from patients including the ones derived from tumors resistant to BRAF inhibitors. Moreover, CRO15 was able to decrease viability of cells lines from a broad range of cancer types. This compound acts by two distinct mechanisms. First by activating the AMPK pathway induced by a mitochondrial disorder. Second by inhibition of MELK kinase activity, which induces cell cycle arrest and activation of DNA damage repair pathways by p53 and REDD1 activation. All of these mechanisms activate autophagic and apoptotic processes resulting in melanoma cell death. The strong efficacy of CRO15 to reduce the growth of melanoma xenograft sensitive or resistant to BRAF inhibitors opens interesting perspective.

Suicide attempts in chronically depressed individuals: What are the risk factors?

Chronically depressed individuals have a high suicide risk. However, it is an open question whether previously observed risk factors for suicide attempts also apply to chronic depression or whether there are specific risk factors related to chronic-recurrent illness. We drew from a large group of chronically depressed individuals seeking psychotherapy to investigate demographic and psychological factors related to previous suicide attempts. Participants took part in the SCID and filled out established questionnaires. Among 368 chronically depressed individuals (68.7% women; Mage = 40.95 years), 75 participants (19.4%) reported previous suicide attempts. Men were more likely to have used violent methods. We tested the links of having attempted suicide with different variables using logistic regression analyses. Our findings corroborate previously observed risk factors (e.g. sexual abuse, personality disorders) and suggest other risk factors which could be especially relevant in chronic depression (e.g. depression severity, interpersonal problems, self-injurious behavior, and overall years of depression). Other risk factors from previous studies were not related to suicidal behavior within our sample (e.g. anxiety disorders, PTSD). Thus, mental health professionals should be aware that risk factors for suicidal behavior might vary between diagnosis groups and that chronic illness might be a risk factor in itself.

PGC1α Inhibits Polyamine Synthesis to Suppress Prostate Cancer Aggressiveness.

Although tumorigenesis is dependent on the reprogramming of cellular metabolism, the metabolic pathways engaged in the formation of metastases remain largely unknown. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) plays a pleiotropic role in the control of cancer cell metabolism and has been associated with a good prognosis in prostate cancer. Here, we show that PGC1α represses the metastatic properties of prostate cancer cells via modulation of the polyamine biosynthesis pathway. Mechanistically, PGC1α inhibits the expression of c-MYC and ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme for polyamine synthesis. Analysis of in vivo metastases and clinical data from patients with prostate cancer support the proposition that the PGC1α/c-MYC/ODC1 axis regulates polyamine biosynthesis and prostate cancer aggressiveness. In conclusion, downregulation of PGC1α renders prostate cancer cells dependent on polyamine to promote metastasis. SIGNIFICANCE: These findings show that a major regulator of mitochondrial metabolism controls polyamine synthesis and prostate cancer aggressiveness, with potential applications in therapy and identification of new biomarkers.

The metabolic modulator PGC-1α in cancer.

The peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is a central modulator of cell metabolism. It regulates mitochondrial biogenesis and oxidative metabolism. Modifications and adaptations in cellular metabolism are hallmarks of cancer cells, thus, it is not surprising that PGC-1α plays a role in cancer. Several recent articles have shown that PGC-1α expression is altered in tumors and metastasis in relation to modifications in cellular metabolism. The potential uses of PGC-1α as a therapeutic target and a biomarker of the advanced form of cancer will be summarized in this review.

UBTD1 is a mechano-regulator controlling cancer aggressiveness.

Ubiquitin domain-containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin-proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell-cell contacts, and the protein is associated with ß-catenin at cell junctions. Yes-associated protein (YAP) is a major cell mechano-transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase ß-TrCP Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2-dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the in cellulo results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression.

Sirtuin 7: a new marker of aggressiveness in prostate cancer.

Predictive biomarkers for advanced prostate cancer (PCa) are still missing. The sirtuin 7 (SIRT7) has been linked to tumorogenesis but its role in prostate cancer is poorly documented. To determine if SIRT7 can be a biomarker for aggressive prostate cancer and plays a role in PCa aggressiveness. We analyzed the expression of SIRT7 by immunohistochemistry in 57 patients comparing healthy with adjacent cancer tissue. SIRT7 levels were significantly elevated in tumors and its expression was positively associated with the grade. We also demonstrated that the knock down of SIRT7 decreased the migration of DU145 and PC3 cells (two androgen-independent prostate cancer cell lines) whereas the overexpression of the native protein but not the mutated form increased the cell migration and the invasion of the poorly aggressive prostate cancer cell line LNCaP. Finally, we also showed that SIRT7 overexpression induced the resistance to docetaxel. Our results demonstrate that SIRT7 promotes prostate cancer cell aggressiveness and chemoresistance and suggest that SIRT7 is a good predictive biomarker of PCa aggressiveness.

The energy disruptor metformin targets mitochondrial integrity via modification of calcium flux in cancer cells.

Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis. Metformin is an energy disruptor targeting complex I of the respiratory chain. We demonstrate that metformin induces endoplasmic reticulum (ER) stress, calcium release from the ER and subsequent uptake of calcium into the mitochondria, thus leading to mitochondrial swelling. Metformin triggers the disorganization of the cristae and inner mitochondrial membrane in several cancer cells and tumors. Mechanistically, these alterations were found to be due to calcium entry into the mitochondria, because the swelling induced by metformin was reversed by the inhibition of mitochondrial calcium uniporter (MCU). We also demonstrated that metformin inhibits the opening of mPTP and induces mitochondrial biogenesis. Altogether, the inhibition of mPTP and the increase in mitochondrial biogenesis may account for the poor pro-apoptotic effect of metformin in cancer cells.