Matrix metalloproteinases (MMPs), together with their endogenous inhibitors (TIMPs) form an enzymatic system that plays an important role in a variety of physiological and pathological conditions. These proteins are also expressed in the brain, especially under pathological conditions, in which glia as well as invading in¯ammatory cells provide the major source of the MMP activity. Surprisingly little is known about the MMP function(s) in adult neuronal physiology. This review describes available data on this topic, which is presented in a context of knowledge about the MMP/TIMP system in other organs as well as in brain disorders. An analysis of the MMP and TIMP expression patterns in the brain, along with a consideration of their regulatory mechanisms and substrates, leads to the proposal of possible roles of the MMP system in the brain. This analysis suggests that MMPs may play an important role in the neuronal physiology, especially in neuronal plasticity, including their direct participation in the remodeling of synaptic connectionsÐa mechanism pivotal for learning and memory.

Estrogens play important roles in the brain, acting through two receptor types, ERalpha and ERbeta, both recognized as transcription factors. In this study, we investigated the ERbeta mRNA and protein expression in the male and female rat brain, focusing on the hippocampus, and comparing with well-known ERalpha expression patterns. Extranuclear ERbeta localization, as shown by light microscopic immunocytochemistry and tissue fractionation experiments, was noted in the hippocampus, whereas nuclear ERbeta was present in the amygdala. Despite these marked differences in subcellular localizations, similar expression levels of ERbeta proteins as well as the profile of ERbeta mRNA isoforms were observed in the two brain structures. ERalpha was localized to the nucleus more so than ERbeta, yet not without an extranuclear component. Our results suggest that cytoplasmic estrogen receptors may play an important role in hippocampal physiology.

Estrogens play an important role in the brain function acting through two receptor types, ERalpha and ERbeta, both well-recognized as transcription factors. In this study, we investigated the ERbeta mRNA and protein levels in the rat hippocampus by using two in vivo models that are known to affect synapse formation. Natural estrous-proestrous cycle was used as a model in which a marked decrease in the density of hippocampal synapses was previously observed between proestrus and estrus. We have found that ERbeta mRNA and protein were displayed in high levels in the estrus and in low levels in the proestrous phase. By applying kainic acid (KA) to adult rats, we demonstrated that up-regulation of ERbeta mRNA and protein in hippocampal CA regions was vulnerable to KA-induced excitotoxicity. Furthermore, we note a concomitant decrease of ERbeta in the excitotoxicity-resistant denate gyrus that undergoes intense plastic changes, including synaptogenesis. These data suggested that decreases in ERbeta expression correlated with increase in synapse formation. This notion has been tested in vitro in hippocampal cultures, in which overexpression of ERbeta by means of gene transfection resulted in the lowering of the dendritic spine density that was elevated by estrogen. In summary, our results suggest that ERbeta inhibits synapse formation in hippocampal neurons.

Endometrial cancer is well known to be estrogen-dependent. Two estrogen receptor types, ER␣ and ER␤, are major mediators of a diversity of biologic functions of estrogen and play an important role in estrogen-dependent tissues and cancers. Cloning of ER␤ was followed by the discovery of a variety of its isoforms. Using real-time RT-PCR, the relative expression levels of ER␤1, ER␤2 (ER␤cx), ER␤3, ER␤4 and ER␤5 were studied. We observed coexpression of ER␤ isoforms in the endometrium and upregulation of the ER␤5 transcript in malignant endometrium. We also observed downregulation of ER␤2⌬5 transcript in neoplastic endometrium, using a semiquantitative method. Our results suggest that analyzing the changes in ER␤ and its isoforms may be important in the diagnosis, prognosis and treatment of endometrial cancer. © 2004 Wiley-Liss, Inc. Key words: endometrial cancer; real-time RT-PCR; estrogen receptor; isoformsEstrogens exert very powerful effects on the growth, differentiation and function of many target tissues in female and male reproductive organs. Their best-described mechanism of action is through ER-mediated gene transcription. This ligand-activated transcription factor is known to exist as ␣ and ␤ proteins, products of 2 separate genes and multiple splice variants of both, 1-7 present in varying cellular patterns. The above accounts for the high complexity of ER action, which is cell-and tissue-specific and may modulate a specific response to estrogen.Estrogen has long been known to stimulate cellular proliferation in the uterus. Indeed, hyperestrogenism is strictly connected with a major risk of endometrial cancer, 8 which is the most common female genital track malignancy in Europe. 9 ER␣ and ER␤ have been identified in normal and neoplastic endometrium. 10 -13 Yet, no conclusive data regarding alterations in their expression in tumors were obtained, as was the case with breast and ovarian tumors, where the levels of ER␤ decline in invasive breast cancer 7,14 -16 as well as in ovarian 17-20 and colon 21,22 cancers. With the increasing knowledge of the mechanism of steroid receptors, the analysis of isoforms, products of alternative splicing of ER␣ and ER␤, is steadily gaining acceptance as a marker for tumor prognosis and a guide for best choice of treatment. For example, ER␣, which lacks exon 5, has been associated with breast cancer, 23 as have the ER␤ isoforms ER␤2 (also named ER␤cx) and ER␤2⌬5. 24,25 This suggests that changes in transcript levels of the ER isoforms take place during tumorigenesis and are important both in etiology and in the assessment of cancer invasiveness.We evaluated the mRNA expression of all ER␤ isoforms (referred to as "total ER␤") and of ER␤1, ER␤2, ER␤2⌬5, ER␤3, ER␤4 and ER␤5 in normal and neoplastic endometrium. We refer our findings to histopathologic data (FIGO 1988 criteria 26 ) as well as to menstrual status. We also examined expression of ER␣ and compared the expression of 2 estrogen-dependent genes, AR and PR, between normal and tumor tissues. Our aim was to determine ...

The LIBRETTO-001 trial demonstrated the activity of the selective rearrangement during transfection (RET) inhibitor selpercatinib in advanced RET fusion-positive non-small cell lung cancer (NSCLC) and resulted in the drug’s approval for this indication. A cohort that included neoadjuvant and adjuvant selpercatinib was opened on LIBRETTO-001 for early-stage RET fusion-positive NSCLC with the primary endpoint of major pathologic response. A patient with a stage IB (cT2aN0M0) KIF5B-RET fusion-positive NSCLC received 8 weeks of neoadjuvant selpercatinib at 160 mg twice daily followed by surgery. While moderate regression in the primary tumor (stable disease, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1) was observed radiologically, assessment via an Independent Pathologic Review Committee revealed a pathologic complete response (0% viable tumor). This consensus assessment by three independent pathologists was aided by RET fluorescence in situ hybridization testing of a reactive pneumocyte proliferation showing no rearrangement. Neoadjuvant selpercatinib was well-tolerated with only low-grade treatment-emergent adverse events. The activity of prospective preoperative selpercatinib in this case establishes proof of concept of the potential utility of RET inhibitor therapy in early-stage RET fusion-positive NSCLC.