Treatment of patients with BRAFV600E-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset.

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.

Waiting for the "liquid revolution" in the adjuvant treatment of colon cancer patients: a review of ongoing trials.

Since colon cancer has a high rate of shedding of tumour fragments into the blood, several research efforts are now focused on the investigation of the minimal residual disease through the detection of ctDNA to tailor the adjuvant therapy of colon cancer patients and optimize its cost/effectiveness balance. The negative prognostic impact of detectable ctDNA in patients' blood after radical surgery for colon cancer is well established. Several clinical trials adopting heterogeneous designs and techniques are now ongoing to translate promises into daily practice by answering five general questions: i) is a ctDNA-guided decision making efficacious in the post-operative management of colon cancer patients? ii) are de-escalation strategies possible in ctDNA-negative cases? iii) are escalation strategies useful to improve the prognosis of ctDNA-positive patients? iv) when MRD is identified at the end of the adjuvant chemotherapy, is another post-adjuvant systemic therapy efficacious? v) can we exploit ctDNA technologies in the follow up of colon cancer patients? This review focuses on currently ongoing trials and how their results may affect the ctDNA "liquid revolution" of early colon cancer.

Heart Rate Variability reveals the fight between racially biased and politically correct behaviour.

In this study, we explored vagally-mediated heart rate variability (vmHRV) responses, a psychophysiological index of cognitive self-regulatory control, to map the dynamics associated with empathic responses for pain towards an out-group member. Accordingly, Caucasian participants were asked to judge the experience of African and Caucasian actors touched with either a neutral or a harmful stimulus. Results showed that (1) explicit judgment of pain intensity in African actors yielded higher rating score and (2) took longer time compared to Caucasian actors, (3) these behavioural outcomes were associated with a significant increment of RMSSD, Log-HF-HRV and HF-HRV n.u., (4) resting HF-HRV n.u. predicted the participants' lag-time to judge painful stimulations delivered to African actors. Interestingly, these dynamics were associated with a measure of implicit racial attitudes and were, in part, abolished when participants performed a concurrent task during videos presentation. Taken together our results support the idea that a cognitive effort is needed to self-regulate our implicit attitude as predicted by the 'Contrasting Forces Model'.

A new diffractometer for diffuse scattering studies on the ID28 beamline at the ESRF.

A new diffractometer is now available to the general user community at the ESRF. The new diffractometer is a side station of the high-resolution inelastic X-ray scattering spectrometer on beamline ID28 and is located in the same experimental hutch. Both instruments can be operated simultaneously. The new diffractometer combines a fast and low-noise hybrid pixel detector with a variable diffraction geometry. The beam spot on the sample is 50 µm × 50 µm, where focusing is achieved by a combination of Be lenses and a KB mirror. Wavelengths from 0.5 to 0.8 Šcan be used for the diffraction experiments. The setup is compatible with a variety of sample environments, allowing studies under non-ambient conditions. The diffractometer is optimized to allow a rapid survey of reciprocal space and diffuse scattering for the identification of regions of interest for subsequent inelastic scattering studies, but can also be employed as a fully independent station for structural studies from both powder and single-crystal diffraction experiments. Several software packages for the transformation and visualization of diffraction data are available. An analysis of data collected with the new diffractometer shows that the ID28 side station is a state-of-the-art instrument for structural investigations using diffraction and diffuse scattering experiments.

Penicillium and Talaromyces endophytes from Tillandsia catimbauensis, a bromeliad endemic in the Brazilian tropical dry forest, and their potential for L-asparaginase production.

This study was conducted to report the richness of endophytic Penicillium and Talaromyces species isolated from Tillandsia catimbauensis, a bromeliad endemic in the Brazilian tropical dry forest (Caatinga), to verify their ability to produce the enzyme L-asparaginase and to partially optimise the production of biomass and L-asparaginase of the best enzyme producer. A total of 184 endophytes were isolated, of which 52 (29%) were identified through morphological and phylogenetic analysis using ß-tubulin sequences into nine putative species, four in Penicillium and five in Talaromyces. Talaromyces diversus and T. cf. cecidicola were the most frequent taxa. Among the 20 endophytic isolates selected for L-asparaginase production, 10 had the potential to produce the enzyme (0.50-2.30 U/g), especially T. cf. cecidicola URM 7826 (2.30 U/g) and Penicillium sp. 4 URM 7827 (1.28 U/g). As T. cf. cecidicola URM 7826 exhibited significant ability to produce the enzyme, it was selected for the partial optimisation of biomass and L-asparaginase production. Results of the 23 factorial experimental design showed that the highest dry biomass (0.66 g) was obtained under pH 6.0, inoculum concentration of 1 × 108 and 1% L-proline. However, the inoculum concentration was found to be statistically significant, the pH was marginally significant and the concentration of L-proline was not statistically significant. L-Asparaginase production varied between 0.58 and 1.02 U/g and did not reach the optimal point for enzyme production. This study demonstrates that T. catimbauensis is colonised by different Penicillium and Talaromyces species, which are indicated for enzyme production studies.

Bone marrow failure may be caused by chromosome anomalies exerting effects on RUNX1T1 gene.

BACKGROUND: The majority of the cases of bone marrow failure syndromes/aplastic anaemias (BMFS/AA) are non-hereditary and considered idiopathic (80-85%). The peripheral blood picture is variable, with anaemia, neutropenia and/or thrombocytopenia, and the patients with idiopathic BMFS/AA may have a risk of transformation into a myelodysplastic syndrome (MDS) and/or an acute myeloid leukaemia (AML), as ascertained for all inherited BMFS. We already reported four patients with different forms of BMFS/AA with chromosome anomalies as primary etiologic event: the chromosome changes exerted an effect on specific genes, namely RUNX1, MPL, and FLI1, leading to the disease. RESULTS: We report two further patients with non-hereditary BM failure, with diagnosis of severe aplastic anaemia and pancytopenia caused by two different constitutional structural anomalies involving chromosome 8, and possibly leading to the disorder due to effects on the RUNX1T1 gene, which was hypo-expressed and hyper-expressed, respectively, in the two patients. The chromosome change was unbalanced in one patient, and balanced in the other one. CONCLUSIONS: We analyzed the sequence of events in the pathogenesis of the disease in the two patients, including a number of non-haematological signs present in the one with the unbalanced anomaly. We demonstrated that in these two patients the primary event causing BMFS/AA was the constitutional chromosome anomaly. If we take into account the cohort of 219 patients with a similar diagnosis in whom we made cytogenetic studies in the years 2003-2017, we conclude that cytogenetic investigations were instrumental to reach a diagnosis in 52 of them. We postulate that a chromosome change is the primary cause of BMFS/AA in a not negligible proportion of cases, as it was ascertained in 6 of these patients.

The GRM7 gene, early response to risperidone, and schizophrenia: a genome-wide association study and a confirmatory pharmacogenetic analysis.

The search for biomarkers of response to antipsychotic medications is hindered by difficulties inherent in the topic or related to persistent methodological difficulties, such as high rates of anticipated discontinuation and consequent distortions in the imputation of missing data. Because early response to antipsychotics represents a sufficiently reliable index of the subsequent treatment response in patients with schizophrenia, we undertook a real-world, genome-wide association study (GWAS) with the aim of identifying genetic predictors of response to risperidone after 2 weeks in 86 patients with schizophrenia. Limited to the associations reaching significance in the GWAS, confirmatory analysis relative to risperidone response over 9 months was also designed involving 97 patients (European only) enroled in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genetic substudy. The GWAS revealed a significant association (false discovery rate 0.02) of the single-nucleotide polymorphism rs2133450 inside the GRM7 gene with Emsley's positive domain derived from the positive and negative syndrome scale (PANSS). Patients with the rs2133450 CC genotype presented poorer improvement in the positive domain over 2 weeks, with odds ratios of 12.68 (95% CI, 3.51-45.76) and 6.95 (95% confidence interval (CI), 2.37-20.37) compared with patients with the AA and AC genotypes, respectively. Compared with A homozygotes, rs2133450 C homozygotes enroled in the CATIE-derived confirmatory analysis showed less improvement in Emsley's positive, excited and depression domains, positive and general PANSS subtypes, and total PANSS after 9 months of treatment with risperidone. The original GWAS and the CATIE-derived confirmatory analysis support the proposal that the rs2133450 may have translational relevance as a predictor of response to risperidone.

Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder.

Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance-related processes may be involved in several phenotypes, including the TRD.

Radiosensitivity in lymphoblastoid cell lines derived from Shwachman-Diamond syndrome patients.

Shwachman-Diamond syndrome is an autosomal-recessive disorder characterised by bone marrow failure and a cumulative risk of progression to acute myeloid leukaemia. The Shwachman-Bodian-Diamond syndrome (SBDS) gene, the only gene known to be causative of the pathology, is involved in ribosomal biogenesis, stress responses and DNA repair, and the lack of SBDS sensitises cells to many stressors and leads to mitotic spindle destabilisation. The effect of ionising radiation on SBDS-deficient cells was investigated using immortalised lymphocytes from SDS patients in comparison with positive and negative controls in order to test whether, in response to ionising radiation exposure, any impairment in the DNA repair machinery could be observed. After irradiating cells with different doses of X-rays or gamma-rays, DNA repair kinetics and the residual damages using the alkaline COMET assay and the γ-H2AX assay were assessed, respectively. In this work, preliminary data about the comparison between ionising radiation effects in different patients-derived cells and healthy control cells are presented.

The loss of Tm7sf gene accelerates skin papilloma formation in mice.

The 3ß-hydroxysterol Δ14-reductase, encoded by the Tm7sf2 gene, is an enzyme involved in cholesterol biosynthesis. Cholesterol and its derivatives control epidermal barrier integrity and are protective against environmental insults. To determine the role of the gene in skin cholesterol homeostasis, we applied 12-o-tetradecanoylphorbol-13-acetate (TPA) to the skin of Tm7sf2(+/+) and Tm7sf2(-/-) mice. TPA increased skin cholesterol levels by inducing de novo synthesis and up-take only in Tm7sf2(+/+) mouse, confirming that the gene maintains cholesterol homeostasis under stress conditions. Cholesterol sulfate, one of the major players in skin permeability, was doubled by TPA treatment in the skin of wild-type animals but this response was lost in Tm7sf2(-/-) mice. The expression of markers of epidermal differentiation concomitant with farnesoid-X-receptor and p38 MAPK activation were also disrupted in Tm7sf2(-/-) mice. We then subjected Tm7sf2(+/+) and Tm7sf2(-/-) mice to a classical two-stage skin carcinogenesis protocol. We found that the loss of Tm7sf2 increased incidence and multiplicity of skin papillomas. Interestingly, the null genotype showed reduced expression of nur77, a gene associated with resistance to neoplastic transformation. In conclusion, the loss of Tm7sf2 alters the expression of proteins involved in epidermal differentiation by reducing the levels of cholesterol sulfate.

Presence of membranous vesicles in cat seminal plasma: ultrastructural characteristics, protein profile and enzymatic activity.

This study sought to verify the presence of membranous vesicles in cat seminal plasma by means of transmission electron microscopy and to identify protein profile and some of the enzymatic activities associated with these particles. The transmission electron microscopy observations showed the existence of different sized vesicular membranous structures of more or less spherical shape. These vesicles were surrounded by single-, double- or multiple-layered laminar membranes. The vesicle diameters ranged from 16.3 to 387.4 nm, with a mean of 116.5 ± 70.7 nm. Enzyme activity determinations showed the presence of dipeptilpeptidase IV, aminopeptidase, alkaline and acid phosphatase. To our knowledge, this is the first report that identifies and characterizes the membranous vesicles in cat seminal plasma. However, further studies are necessary to identify the exact site of production of these membranous vesicles in the cat male genital tract and to determine their specific roles in the reproductive events of this species.

Maternal dietary loads of alpha-tocopherol increase synapse density and glial synaptic coverage in the hippocampus of adult offspring.

An increased intake of the antioxidant α-Tocopherol (vitamin E) is recommended in complicated pregnancies, to prevent free radical damage to mother and fetus. However, the anti-PKC and antimitotic activity of α-Tocopherol raises concerns about its potential effects on brain development. Recently, we found that maternal dietary loads of α-Tocopherol through pregnancy and lactation cause developmental deficit in hippocampal synaptic plasticity in rat offspring. The defect persisted into adulthood, with behavioral alterations in hippocampus-dependent learning. Here, using the same rat model of maternal supplementation, ultrastructural morphometric studies were carried out to provide mechanistic interpretation to such a functional impairment in adult offspring by the occurrence of long-term changes in density and morphological features of hippocampal synapses. Higher density of axo-spinous synapses was found in CA1 stratum radiatum of α-Tocopherol-exposed rats compared to controls, pointing to a reduced synapse pruning. No morphometric changes were found in synaptic ultrastructural features, i.e., perimeter of axon terminals, length of synaptic specializations, extension of bouton-spine contact. Glia-synapse anatomical relationship was also affected. Heavier astrocytic coverage of synapses was observed in Tocopherol-treated offspring, notably surrounding axon terminals; moreover, the percentage of synapses contacted by astrocytic endfeet at bouton-spine interface (tripartite synapses) was increased. These findings indicate that gestational and neonatal exposure to supranutritional tocopherol intake can result in anatomical changes of offspring hippocampus that last through adulthood. These include a surplus of axo-spinous synapses and an aberrant glia-synapse relationship, which may represent the morphological signature of previously described alterations in synaptic plasticity and hippocampus-dependent learning.

Association between baseline serum vascular endothelial growth factor levels and response to electroconvulsive therapy.

OBJECTIVE: Several studies have shown that vascular endothelial growth factor (VEGF) is implicated in different neuronal processes involved in major depressive disorder (MDD) and in the mechanisms of action of antidepressants. The aim of this study was to investigate whether VEGF serum levels before treatment might be associated with the antidepressant response. METHOD: Two groups of patients were enrolled. One was composed of 50 MDD patients receiving an antidepressant drug treatment. Illness severity was measured before the treatment (T0) and after 12 weeks (T1). The second group was composed of 67 treatment-resistant depressed (TRD) patients undergoing electroconvulsive therapy (ECT). Illness severity was assessed before the treatment (T0) and 1 month after the end of ECT (T1). Blood samples for VEGF measurements were collected for both groups at the baseline (T0). RESULTS: A significant correlation was observed between baseline VEGF serum levels and the percentage reduction in depressive symptomatology after ECT (P = 0.003). In particular, VEGF levels at baseline were significantly lower in patients showing no response to ECT at follow-up (P = 0.008). No correlation between T0 VEGF concentrations and drug treatment outcome was found. CONCLUSION: Our results suggest that VEGF plays a role in the mechanism of response to ECT.

Ultrastructural and enzymatic activity of membranous vesicles isolated from canine seminal plasma.

The objectives of this study were to verify the presence of membranous vesicles (MV) in canine seminal plasma by mean of transmission electron microscopy (TEM), to describe the ultrastructural characteristics and to identify some enzymatic activity associated with them. Semen samples, collected by digital manipulation from dogs with proven fertility, were pooled and used for membrane vesicles preparation according to conventional procedures. TEM observations showed the existence of vesicular membranous structures of more or less spherical shape with different sizes. These vesicles were surrounded by a single-, double- or multiple-layered laminar membranes. The mean vesicle diameter was 117.6 ± 86.9 nm ranging from 24.4 to 716.6 nm. Enzyme activity determinations showed the presence of adenosine deaminase, 5'-nucleotidase, ADPase, ATPase, dipeptilpeptidase IV, alkaline phosphatase, total acid phosphatase and prostatic acid phosphatase, while the aminopeptidase activity was absent. In conclusion, results of this study, compatible with results from other mammals, showed for the first time the presence of MV, their ultrastructural and enzymatic characteristics in dog seminal plasma.

Effectiveness of cognitive behavioral therapy in the treatment of fibromyalgia syndrome: a meta-analytic literature review.

Fibromyalgia (FM) is a chronic disorder caused by a dysfunction of central nervous system sensitization. This syndrome is characterized by widespread pain and diffuse tenderness, but often also presents fatigue, sleep disturbances, and a whole range of symptoms such as morning stiffness, decreased physical function and dyscognition. FM is usually treated with pharmacological and non-pharmacological treatments. The non-pharmacological interventions include cognitive behavioral therapy (CBT), physiotherapy, acupuncture and patient education programs. In order to evaluate the efficacy of CBT and compare it with other non-pharmacological treatments, we performed a review of the meta-analytic literature. We evaluated the methodological quality of publications found by following the recommendations of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Data showed that CBT does not provide better results than other non-pharmacological treatments on outcomes of pain, fatigue, sleep disturbance and quality of life, at either a short or long-term evaluation. On the contrary, CBT seems to be more effective on symptoms of depression for a short period, whereas it considerably improves the pain self-management and reduces the number of visits to the doctor. The data currently available indicate that cost-effectiveness studies could help us to understand whether the reduction in the number of visits to the doctor could balance the cost of CBT to the health public system.

Shwachman-Diamond syndrome and type 1 diabetes mellitus: more than a chance association?

Shwachman-Diamond syndrome is a rare clinical condition consisting of exocrine pancreatic dysfunction, various degree of pancytopenia, and metaphyseal dysplasia. The majority of Shwachman-Diamond syndrome cases result from mutations in the Shwachman-Bodian-Diamond Syndrome gene. To date, type 1 diabetes mellitus has only been reported in 4 independent cases presenting with Shwachman-Diamond syndrome, 3 of them with molecular confirmation of the diagnosis. We describe 2 unrelated patients with clinical and molecular features typical of Shwachman-Diamond syndrome and type 1 diabetes mellitus. In addition, we report the occurrence rate of type 1 diabetes mellitus in the Italian registry for Shwachman-Diamond syndrome, which is low (3.23%) but increased at least 30-fold over the type 1 diabetes mellitus occurrence rate in the general population. No evidence of a direct correlation between Shwachman-Diamond syndrome and type 1 diabetes mellitus have been reported, therefore the presence of both diseases in the same patient might be a chance association, however we suggest that the defects in immune regulation of Shwachman-Diamond syndrome might play a role in the development of type 1 diabetes mellitus.

The isochromosome i(7)(q10) carrying c.258+2t>c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder, characterized by exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow (BM) dysfunction with an increased risk to develop myelodysplastic syndrome and/or acute myeloid leukaemia (MDS/AML). SDS is caused, in nearly 90% of cases, by two common mutations (that is, c.183_184TA>CT and c.258+2T>C) in exon 2 of the SBDS gene, localized on chromosome 7. Clonal chromosome anomalies are often found in the BM of SDS patients; the most frequent is an isochromosome for long arms of chromosome 7, i(7)(q10). We studied eight patients with SDS carrying the i(7)(q10) who were compound heterozygotes for SBDS mutations. By assessing the parental origin of the i(7)(q10) using microsatellite analysis, we inferred from the results which mutation was present in double dose in the isochromosome. We demonstrate that in all cases the i(7)(q10) carries a double dose of the c.258+2T>C, and we suggest that, as the c.258+2T>C mutation still allows the production of some amount of normal protein, this may contribute to the low incidence of MDS/AML in this subset of SDS patients.

2-Chloroadenosine and human prostate cancer cells.

Cladribine, i.e.2-deoxy-Chloroadenosine is currently in use as chemotherapeutic agent in chronic lymphoid malignancies and pediatric acute myelogenous leukemia whereas the structurally related counterpart, 2-Chloroadenosine, has been less studied. Nevertheless, 2-Chloroadenosine has been shown to be capable of inducing apoptosis in several cell lines by acting either via adenosine receptors or via uptake that is followed by metabolic transformations leading to nucleotide analogues, i.e. antimetabolites effective in the treatment of a variety of malignancies. Triphosphate nucleoside analogues show specificity for cell in S-phase, inhibit DNA synthesis and kill the cells by mechanisms still largely unknown. 2-Chloroadenosine, at low micromolar concentration, acts as a metabolic precursor of an S-phase specific nucleoside analogue in human prostate cancer PC3 cells and inhibits DNA synthesis thereby leading to accumulation of cells in the S-phase. However, although responsible for the acquisition of resistance, the adenosine derivative is capable of sensitising the cells to the action of other antineoplastic agents and the ability of nucleoside analogues to trigger cell cycle arrest can be exploited to maximize cytotoxicity in combination with cell cycle checkpoint disregulators. 2-Chloroadenosine, in combination with Docetaxel, known to improve the survival of hormone-refractory prostate cancer patients, further decreases in vitro PC3 cell proliferation and invasiveness. Moreover, 2-Chloroadenosine is capable of modulating PAR-1 and IL-23 gene expression suggesting a modulation of cancer metastasis and immune system activity. The present review summarizes research performed in our laboratory to propose a novel role for 2-Chloroadenosine as an anticancer agent.

Focus on cyclo(His-Pro): history and perspectives as antioxidant peptide.

Cyclo(His-Pro) is an endogenous cyclic dipeptide structurally related to tyreotropin-releasing hormone that was originally discovered in brain. In the central nervous system it has been described to exert multiple biological activities, which seem to be related to a presynaptic dopaminergic mechanism and include among the others a leptin-like function. It can be found in several body fluids and in the gastrointestinal tract where it has been suggested to act as a gut peptide with influence on the entero-insular axis. The oral administration of cyclo(His-Pro) and zinc was described to improve with a synergistic mechanism the glycaemic control in diabetes. The most intriguing function of this cyclic dipeptide is related with its neuroprotective role that was first reported in traumatic injuries of the spinal cord, and then confirmed in other models of experimental injuries of the nervous system. The mechanism that lies behind the neuroprotective activity of cyclo(His-Pro) remain poorly understood. Recent in vitro studies on rat pheochromocytoma PC12 cells have shown that it is a protective factor against stress stimuli and there is early pre-clinical evidence strongly suggesting that it enhances the expression of small heat shock proteins and antioxidant protection at the cellular level. Future research is underway to better characterize the possible use of this cyclic dipeptide in the therapy of neurodegenerative and metabolic disorders.