Anhedonia and social adaptation predict substance abuse evolution in dual diagnosis schizophrenia

The current study sought to identify the variables, derived from the self-medication hypothesis, which predicted substance abuse evolution during a homogeneous 3-month antipsychotic treatment. Twenty-four patients were diagnosed with schizophrenia and substance abuse (mainly cannabis and alcohol). Substance abuse, psychiatric symptoms, anhedonia, and social adjustment were assessed at baseline and study endpoint. Linear regression analyses were performed. Better social adaptation and worse anhedonia predicted substance abuse improvements. Conversely, greater psychoactive substance (PAS) use predicted endpoint positive and depressive symptoms. These results suggest that: (i) substance abuse interferes with psychiatric prognosis in schizophrenia; and (ii) dual diagnosis treatments leading patients to engage in alternative social activities may render substance abuse less appealing. Further studies are warranted to dissociate the causes and consequences of substance abuse in schizophrenia.     

Conjugation of poly-L-lysine to bacterial cytosine deaminase improves the efficacy of enzyme/prodrug cancer therapy

We previously observed that bacterial cytosine deaminase (bCD) conjugated with multimodal imaging reporter labeled poly-L-lysine (PLL) demonstrated high therapeutic efficacy in an enzyme/prodrug cancer therapeutic strategy. To understand the role of polycationic PLL in the cellular uptake of bCD-PLL conjugate, two control molecules, bCD-BF, without the PLL moiety, and bCD-AcPLL, with all positive charges in PLL neutralized, were prepared. bCD-PLL demonstrated about 50 times higher cellular uptake than that of control molecules in human breast MDA-MB-231 cancer cells. Internalized bCD-PLL demonstrated high enzymatic stability in cell cultures as indicated by significant cytotoxicity after addition of prodrug, whereas no obvious cytotoxicity was detected by control molecules. These data indicate that conjugated PLL not only provides a multivalent modification platform to facilitate the delivery of a high payload of imaging reporters or targeting moieties without compromising enzymatic activity but also enhances therapeutic efficacy by accelerating the intracellular uptake of prodrug-activating enzyme.     

A role for phospholipase D1 in neurotransmitter release

Phosphatidic acid produced by phospholipase D (PLD) as a result of signaling activity is thought to play a role in membrane vesicle trafficking, either as an intracellular messenger or as a cone-shaped lipid that promotes membrane fusion. We recently described that, in neuroendocrine cells, plasma membrane-associated PLD1 operates at a stage of Ca(2+)-dependent exocytosis subsequent to cytoskeletal-mediated recruitment of secretory granules to exocytotic sites. We show here that PLD1 also plays a crucial role in neurotransmitter release. Using purified rat brain synaptosomes subjected to hypotonic lysis and centrifugation, we found that PLD1 is associated with the particulate fraction containing the plasma membrane. Immunostaining of rat cerebellar granule cells confirmed localization of PLD1 at the neuronal plasma membrane in zones specialized for neurotransmitter release (axonal neurites, varicosities, and growth cone-like structures). To determine the potential involvement of PLD1 in neurotransmitter release, we microinjected catalytically inactive PLD1(K898R) into Aplysia neurons and analyzed its effects on evoked acetylcholine (ACh) release. PLD1(K898R) produced a fast and potent dose-dependent inhibition of ACh release. By analyzing paired-pulse facilitation and postsynaptic responses evoked by high-frequency stimulations, we found that the exocytotic inhibition caused by PLD1(K898R) was not the result of an alteration in stimulus-secretion coupling or in vesicular trafficking. Analysis of the fluctuations in amplitude of the postsynaptic responses revealed that the PLD1(K898R) blocked ACh release by reducing the number of active presynaptic-releasing sites. Our results provide evidence that PLD1 plays a major role in neurotransmission, most likely by controlling the fusogenic status of presynaptic release sites.     

Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Uveal melanoma is associated with a high mortality rate once metastases occur, with over >90% of metastatic patients dying within less than 1 year from metastases to the liver. The intraarterial hepatic (iah) administration of the alkylating agent fotemustine holds some promise with response rates of 36% and median survival of 15 months. Here, we investigated whether the DNA-repair-protein MGMT may be involved in the variability of response to fotemustine and temozolomide in uveal melanoma. Epigenetic inactivation of MGMT has been demonstrated to be a predictive marker for benefit from alkylating agent therapy in glioblastoma. We found a methylated MGMT promoter in 6% of liver metastases from 34 uveal melanoma patients. The mean MGMT activity measured in liver metastases with negligible liver tissue content was significantly lower than in liver tissue (146 versus 523 fmol/mg protein, p = 0.002). Expression of the MGMT protein was detectable in 50% of 88 metastases by immunohistochemistry on a tissue microarray. Expression was heterogeneous, and in accordance with MGMT activity data, usually lower than in the surrounding liver. Differential MGMT activity/expression between metastasis and liver tissue and more efficient depletion of MGMT with higher doses of alkylating agent therapy using iah delivery may provide the pharmacologic window for the higher response rate. However, these results do not support MGMT methylation status or protein expression as predictive markers for treatment outcome to iah chemotherapy with alkylating agents.     

Melanoma affinity in mice and immunosuppressed sheep of [(125)I]N-(4-dipropylaminobutyl)-4-iodobenzamide, a new targeting agent

The increasing incidence of melanoma and the lack of effective therapy have prompted the development of new vectors, more specific to the pigmented tumor, for early detection and treatment. Targeted agents have to exhibit a rapid, high tumor uptake, long tumor retention and rapid clearance from nontarget organs. This joint work presents results obtained with a new melanoma targeting agent, [(125)I]-N-(4-dipropylaminobutyl)-4-iodobenzamide or [(125)I]BZ18. After labeling with a high specific activity, the biodistribution of the compound was investigated in two animal models, the mouse and the sheep. Melanotic tumor retention was observed lasting several days. We visualized the internalization of the agent inside the melanosomes by secondary ion mass spectroscopy imaging, we measured the affinity constants of [(125)I]BZ18 on a synthetic melanin model and we demonstrated a radiotoxic effect of this labeled agent on B16F0 melanoma cell culture due to its cellular internalization. From this work, [(125)I]BZ18 appeared a promising melanoma targeting agent in the nuclear medicine field.     

A “class action” against the microenvironment: do cancer cells cooperate in metastasis?

The authors review how cancer cells may cooperate in metastasis by means of microenvironmental changes. The main mechanisms underlying this cooperation are clustered migration of cancer cells, extracellular matrix degradation, paracrine loops of released signaling factors and/or induction of adhesion molecules on stromal cells. Another critical factor could be temporal cooperation: successive waves of cancer cells may induce progressive conditioning of the microenvironment. The “class action” of cancer cells against the microenvironment involves successive steps of the metastatic process: invasion of the primary tumor microenvironment, collective migration through the extracellular matrix, blood vessel disruption, vascular or lymphatic tumor emboli, establishment of a premetastatic niche by secreted factors and endothelial precursor recruitment, induction of cell adhesion molecule expression in endothelial cells, extravasation, micrometastasis dormancy and establishment of a new growth in distant sites. As a result, after completion of the metastatic process, the series of microenvironmental changes from the primary tumor to the metastatic site may promote colonization of metastases by nonmetastatic cancer cells of the primary tumor.     

Extracellular gadolinium-based contrast media: differences in diagnostic efficacy

Since the introduction of the first gadolinium-based contrast agent (Gd–CA) in 1988 it has become clear that these agents significantly improve the diagnostic efficacy of MRI. Studies on single agents have shown that, in comparison to unenhanced sequences, all agents help to improve the detection and delineation of lesions which can alter diagnosis in up to 40% of patients. Doubling or tripling the standard dose of 0.1 mmol/kg body weight may be beneficial for selected indications (e.g. brain perfusion, equivocal single dose study in MRI for brain metastasis, small vessel MR angiography). A more limited number of studies have compared the various agents. These studies do not show clinically significant differences in diagnostic efficacy between the various extracellular Gd–CA. Agents with higher concentration or protein binding may be relatively better suitable for selected applications (e.g. perfusion MRI). The higher relaxivity agents may be used in somewhat lower doses than the extracellular agents.     

Management Strategies for Older Patients with Low-Risk Early-Stage Breast Cancer: A Physician Survey

When managing older patients with lower-risk hormone-receptor-positive (HR+), HER2 negative (HER2−) early-stage breast cancer (EBC), the harms and benefits of adjuvant therapies should be taken into consideration. A survey was conducted among Canadian oncologists on the definitions of “low risk” and “older”, practice patterns, and future trial designs. We contacted 254 physicians and 21% completed the survey (50/242). Most respondents (68%, 34/50) agreed with the definition of “low risk” HR+/HER2− EBC being node-negative and either: ≤3 cm and low histological grade, ≤2 cm and intermediate grade, or ≤1 cm and high grade. The most popular chronological and biological age definition for older patients was ≥70 (45%, 22/49; 45% 21/47). In patients ≥ 70 with low risk EBC, most radiation and medical oncologists would recommend post-lumpectomy radiotherapy (RT) and endocrine therapy (ET). Seventy-eight percent (38/49) felt that trials are needed to evaluate RT and ET’s role in patients ≥ 70. The favored design was ET alone, vs. RT plus ET (39%, 15/38). The preferred primary and secondary endpoints were disease-free survival and quality of life, respectively. Although oncologists recommended both RT and ET, there is interest in performing de-escalation trials in patients ≥ 70.