Effects of imipramine on cancer patients over-expressing Fascin1; description of the HITCLIF clinical trial.

Background: Tumor invasion and metastasis are responsible for the majority of cancer-related deaths. The identification of molecules involved in these processes is crucial to design effective treatments that can halt the progression of cancer. To spread and metastasize, tumor cells must restructure their cytoskeleton and emit protrusions. A key molecule in this process of creating these invading structures is Fascin1, the main protein involved in the formation of actin cytoskeleton bundles and a consistent marker of bad prognosis in several types of cancer. Recent studies have shown that imipramine, an FDA- and EMA-approved antidepressant, can block Fascin1and prevent the formation of actin bundles, making it a promising candidate for the treatment of Fascin1-expressing cancers. As a result, a clinical trial will be conducted to assess the efficacy of imipramine being the first experimental clinical study selecting patients based on Fascin1 expression. Methods: The HITCLIF trial is a multicenter, double-blind, placebo-controlled, randomized and non-commercial phase II clinical trial conducted in parallel groups to evaluate the effectiveness of the tricyclic antidepressant imipramine as anti-invasive agent in the treatment of localized colon, rectal and triple negative breast cancer patients with overexpression of Fascin1. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive imipramine or placebo. Patients will be stratified into 2 groups according to whether administration of imipramine is concomitant with neoadjuvant chemotherapy regimen. Group A will receive imipramine alone without neoadjuvant chemotherapy, while Group B will receive imipramine treatment along with the standard neoadjuvant chemotherapy regimen. The primary endpoint of the trial is the grade of alteration in the prognostic histopathological features at invasive margins (tumor budding, cytoplasmic pseudo-fragments, tumor growth pattern, and peritumoral lymphocytic infiltration). Discussion: Fascin1 is an interesting therapeutical target as it plays a causative role in the invasion and metastasis of cancer cells. Moreover, its expression is virtually absent in normal epithelia but highly expressed in cancer with bad prognosis. In silico, in vitro and in vivo studies by our group have demonstrated that the antidepressant imipramine has Fascin1-dependant anti-invasive and anti-metastatic effects in colorectal cancer cells. Now we are recruiting patients in a clinical trial based on Fascin1 over-expression in which administration of imipramine will be carried out during the period between the diagnosis biopsy and surgical resection to explore the drug effects on tumor invasive front. Clinical trial registration: https:///www.clinicaltrialsregister.eu/ctr-search/trial/2021-001328-17/ES, identifier 2021-001328-17.

Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment.

Growing evidence shows that nerves play an active role in cancer development and progression by altering crucial molecular pathways and cell functions. Conversely, the use of neurotropic drugs, such as tricyclic antidepressants (TCAs), may modulate these molecular signals with a therapeutic purpose based on a direct antitumoral effect and beyond the TCA use to treat neuropathic pain in oncology patients. In this review, we discuss the TCAs' safety and their central effects against neuropathic pain in cancer, and the antitumoral effects of TCAs in in vitro and preclinical studies, as well as in the clinical setting. The current evidence points out that TCAs are safe and beneficial to treat neuropathic pain associated with cancer and chemotherapy, and they block different molecular pathways used by cancer cells from different locations for tumor growth and promotion. Likewise, ongoing clinical trials evaluating the antineoplastic effects of TCAs are discussed. TCAs are very biologically active compounds, and their repurposing as antitumoral drugs is a promising and straightforward approach to treat specific cancer subtypes and to further define their molecular targets, as well as an interesting starting point to design analogues with increased antitumoral activity.

Update on Safety Profiles of Vitamins B1, B6, and B12: A Narrative Review.

The neurotropic B vitamins B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) are essential for proper functioning of the nervous system. Deficiencies may induce neurological disorders like peripheral neuropathy (PN) and mainly occur in vulnerable populations (eg, elderly, diabetics, alcoholics). As epidemiologic cohort studies raised safety concerns about vitamin B6/B12 intake being potentially associated with increased risks of hip fracture (HF) and lung cancer (LC), we explored these aspects and performed comprehensive literature searches. However, we suggest not to neglect actual high-risk factors (eg, smoking in LC, higher age in HF) by focusing on individual nutrients, but to examine the complex interaction of numerous factors involved in disease development. Because it warrants continued consideration, we also provide an update on neurotoxicity associated with vitamin B6. We consider that neurological side effects due to vitamin B6 intake are rare and only occur with high daily doses and/or longer treatment duration. The benefit-risk ratio of high-dose treatment with neurotropic B vitamins in indications like PN is therefore considered advantageous, particularly if dosing recommendations are followed and serum levels monitored.

Chronic graft-versus-host disease could ameliorate the impact of adverse somatic mutations in patients with myelodysplastic syndromes and hematopoietic stem cell transplantation.

Somatic mutations in patients with myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSTC) are associated with adverse outcome, but the role of chronic graft-versus-host disease (cGVHD) in this subset of patients remains unknown. We analyzed bone marrow samples from 115 patients with MDS collected prior to HSCT using next-generation sequencing. Seventy-one patients (61%) had at least one mutated gene. We found that patients with a higher number of mutated genes (more than 2) had a worse outcome (2 years overall survival [OS] 54.8% vs. 31.1%, p = 0.035). The only two significant variables in the multivariate analysis for OS were TET2 mutations (p = 0.046) and the development of cGVHD, considered as a time-dependent variable (p < 0.001), correlated with a worse and a better outcome, respectively. TP53 mutations also demonstrated impact on the cumulative incidence of relapse (CIR) (1 year CIR 47.1% vs. 9.8%, p = 0.006) and were related with complex karyotype (p = 0.003). cGVHD improved the outcome even among patients with more than 2 mutated genes (1-year OS 88.9% at 1 year vs. 31.3%, p = 0.02) and patients with TP53 mutations (1-year CIR 20% vs. 42.9%, p = 0.553). These results confirm that cGVHD could ameliorate the adverse impact of somatic mutations in patients with MDS with HSCT.

An early increase of CD56bright natural killer subset as dominant effect and predictor of response to extracorporeal photopheresis for graft-versus-host disease.

BACKGROUND: CD56bright natural killer (NK) regulatory cells were recently shown to display a differential impact on the risk of developing extensive chronic graft-versus-host disease (GVHD). To date no study has definitively established which immune populations are most responsible for the immunomodulatory effects or response to extracorporeal photopheresis (ECP) for GVHD. STUDY DESIGN AND METHODS: To test the role of CD56bright NK cells in ECP, a prospective enhanced flow cytometry follow-up of immune subsets (CD19+, CD3+, CD3+/CD4+, CD3+/CD8+, CD3-/CD56+, CD3-/CD56bright , and CD3-/CD56dim ) was performed in 32 patients with GVHD who underwent 552 procedures. RESULTS: An early increase of CD56bright NK cells was found as a hallmark effect to ECP, particularly during the first 3 months of treatment. This was also supported by the ability to predict for complete responses when this increase was expressed as a higher CD56bright versus CD56dim NK cells ratio. Among the immune subsets tested, the only variable that had direct influence on response to ECP was a CD56bright/dim ratio more than 0.16 (hazard ratio [HR] 4.32, p = 0.014; HR 5.8, p = 0.007, at 2 and 3 months of ECP treatment, respectively). CONCLUSION: These findings argue for exploring strategies for priming a CD56bright NK cell expansion during ECP and providing additional and potentially relevant data for revisiting the underpinning cellular mechanisms of ECP that could generate that expansion.

Tratamiento temprano de la mordida abierta anterior con aparatología ortopédica funcional. Reporte de caso / Early treatment of anterior open bite with functional orthopedic appliances. A case report

En las mordidas abiertas anteriores se tienen alteradas las relaciones oclusales y existen discrepancias desde las bases óseas que ocasionan una parafunción muscular desencadenando un desequilibrio en todo el sistema estomatognático. Al intervenir de manera temprana esta alteración, se logra además de recuperar las funciones normales, proporcionar cambios faciales que mejoran la estética del paciente. Es importante que el profesional recuerde la complejidad de la etiología multifactorial de las mordidas abiertas anteriores para lograr su corrección y tener una estabili - dad alargo plazo. Para el tratamiento se han descrito distintas terapéuticas como - ortodoncia, ortopedia funcional e incluso intervenciones quirúrgicas. Se presenta un caso clínico de un paciente de 7 años de edad, género masculino, quien consulta para tratamiento ortopédico, los hallazgos clínicos y cefalométricos determinan una maloclusión clase II con mordida abierta anterior esquelética, patrón respiratorio con predomio oral y deglución atípica. El tratamiento ortopédico se realizó con apara - tología funcional usando Simoes Network 2 (SN2). Al primer año de seguimiento ya se observan cambios clínicos faciales e intraorales, y al siguiente año los cambios radiográficos reflejan la mejoría en las relaciones craneofaciales y funcionales.

Anterior open bites are characterized by altered occlusal relationships. They cau - se discrepancies at the jaws that trigger a parafunctional muscular imbalance throughout the stomatognathic system. When this alteration is intervened early, again of normal functions can be achieved but also intervention causes facial changes that improve the aesthetics of the patient. It is important to take into consideration the complexity and the multifactorial etio - logy of anterior open bites to achieve their correction and long-term clinical stability. Different therapeutic approaches have been described for the treatment of anterior open bites including: orthodontics, functional orthopedics and even surgical interven - tions. Here We present a clinical case of a seven-year-old male patient who consulted for orthopedic treatment of an anterior open bite. Clinical findings determined a Class II cephalometric malocclusion with anterior skeletal open bite, oral respiratory pattern and atypical swallowing. Orthopedic treatment was done using Simoes Network 2 (SN2) functional appliances. At the first year of follow-up facial and intraoral clini - cal changes were noted. During the second year of follow-up radiographic changes showed improvement in craniofacial and functional relationships.

Agenesia de primeros y segundos molares permanentes: Revisión de literatura y reporte de casos / Agenesis of first and second permanent molars: Literature review and cases reports

La agenesia dental es la ausencia de uno o más dientes en la dentición temporal o permanente, es la alteración dental más fre - cuente, se puede presentar de forma aislada o como parte de un síndrome genético, la incidencia de agenesia en dientes perma - nentes varía de 1,6 -9,6%, excluyendo los terceros molares, mientras que en dentición temporal el intervalo es de 0,5 a 0,9%. Los factores que actualmente se relacionan con la agenesia dental, son los genes y sus vías de señalización. Específicamente el Pax9 se ha asociado a la falta de molares permanentes. La agenesia de los primeros y segundos molares permanentes aunque no es muy frecuente ha sido reportada en la literatura en forma aislada y puede resultar en una maloclusión, alterando el equilibrio. Por lo tanto, el diagnóstico temprano es fundamental para instaurar un plan de tratamiento adecuado que permita guiar la erupción del resto de los dientes y evitar la aparición de secuelas por causa de la agenesia. Se presentan cuatro casos clínicos de pacientes con agenesia de pri- meros y segundos molares permanentes para complementar la revisión de literatura...(Au)

Tooth agenesis is the absence of one or more teeth in temporary or permanent den - tition. This anomaly in craniofacial malfor - mations is more frequent, that may occur as an isolated anomaly or as part of a genetic syndrome. The incidence of agenesis of permanent teeth varies1.6-9.6%, excluding third molars, while in primary dentition the range is 0.5 to 0.9%. The factors that are related to dental agenesis, are the genes and signaling pathways. Specifically Pax9 has been associated with the lack of permanent molars. Agenesis of the first and second permanent molars is not very common but has been reported in the literature and can be isolated or causing malocclusion. Therefore, early diagnosis is essential to establish a treatment plan to help guide the eruption of other teeth and prevent sequel due to agenesis. Four clinical cases are pre - sented of patients with agenesis of first and second permanent molars to complement the literature review...(Au)