Calcium dynamics and circadian rhythms in suprachiasmatic nucleus neurons

The hypothalamic suprachiasmatic nucleus (SCN) has a pivotal role in the mammalian circadian clock. SCN neurons generate circadian rhythms in action potential firing frequencies and neurotransmitter release, and the core oscillation is thought to be driven by "clock gene" transcription-translation feedback loops. Cytosolic Ca2+ mobilization followed by stimulation of various receptors has been shown to reset the gene transcription cycles in SCN neurons, whereas contribution of steady-state cytosolic Ca2+ levels to the rhythm generation is unclear. Recently, circadian rhythms in cytosolic Ca2+ levels have been demonstrated in cultured SCN neurons. The circadian Ca2+ rhythms are driven by the release of Ca2+ from ryanodine-sensitive internal stores and resistant to the blockade of action potentials. These results raise the possibility that gene translation/transcription loops may interact with autonomous Ca2+ oscillations in the production of circadian rhythms in SCN neurons

CB2 cannabinoid receptor activation promotes colon cancer progression via AKT/GSK3β signaling pathway

The pharmacological activation of the cannabinoid receptor type 2, CB2, has been shown to elicit anti-tumoral mechanisms in different cancer types. However, little is known about its endogenous role in tumor pathophysiology, and different studies have attributed pro-tumorigenic properties to this receptor. In a previous work, we showed that CB2 expression is a poor prognostic factor in colon cancer patients. Here we report that activation of CB2 with low doses of specific agonists induce cell proliferation and favor the acquisition of aggressive molecular features in colon cancer cells. We show that sub-micromolar concentrations of CB2-specific agonists, JWH-133 and HU-308, promote an increase in cell proliferation rate through the activation of AKT/PKB pathway in colon cancer in vitro and in vivo. AKT activation promotes GSK3β inhibition and thus, a more aggressive cell phenotype with the subsequent elevation of SNAIL levels, E-cadherin degradation and β-catenin delocalization from cell membrane. Taken together, our data show that CB2 activation with sub-micromolar doses of agonists, which could be more similar to endogenous levels of cannabinoids, promote colon cancer progression, implicating that CB2 could have a pro-tumorigenic endogenous role in colon cancerThis work was supported by grants from Fondo de Investigaciones Sanitarias (ISCIII-PI10/00879 to JMG; Plan Nacional de I+D+I 2008-2011, FEDER funds co-financed), Red Temática de Investigación Cooperativa en Cáncer (ISCIII-RETIC RD12/0036/0041; Plan Estatal de I+D+I 2013-2016, FEDER funds cofinanced). JMG and PM were supported by ISCIII CP08/00217 and JR14/0018 contracts, respectively. EMM was recipient of ISCIII PFIS PhD studentship (FI11/00696) (Plan Nacional de I+D+I 2008-2011, FEDER funds co-financed); AMR was recipient of PhD contract from Department of Medical Oncology of H.U. Puerta de Hierro; VC was recipient of attending physician contract in Medical Oncology Department from H.U. Puerta de Hierro; MP was supported by Universidad Autónoma de Madrid (UAM) with Full Professor contrac

Atezolizumab Plus Bevacizumab as First-line Treatment for Patients With Metastatic Nonsquamous Non-Small Cell Lung Cancer With High Tumor Mutation Burden: A Nonrandomized Controlled Trial

Bevacizumab; Lung neoplasms; Neoplasm metastasisBevacizumab; Neoplasias pulmonares; Metástasis neoplásicaBevacizumab; Càncer de pulmó; Metàstasi neoplàsicaImportance: Antiangiogenic drug combinations with anti-programmed cell death 1 protein and anti-programmed cell death 1 ligand 1 (PD-L1) agents are a novel treatment option for lung cancer. However, survival remains limited, and the activity of these combinations for tumors with high tumor mutation burden (TMB) is unknown. Objective: To assess the clinical benefits and safety of atezolizumab plus bevacizumab for patients with high-TMB advanced nonsquamous non-small cell lung cancer (NSCLC). Design, setting, and participants: This multicenter, single-arm, open-label, phase 2 nonrandomized controlled trial (Atezolizumab Plus Bevacizumab in First-Line NSCLC Patients [TELMA]) included treatment-naive patients aged 18 years or older with confirmed stage IIIB-IV nonsquamous NSCLC with TMB of 10 or more mutations/megabase and no EGFR, ALK, STK11, MDM2, or ROS1 alterations. From May 2019 through January 2021, patients were assessed at 13 sites in Spain, with follow-up until February 28, 2022. Interventions: Participants were given atezolizumab, 1200 mg, plus bevacizumab, 15 mg/kg, on day 1 of each 21-day cycle. Treatment was continued until documented disease progression, unacceptable toxic effects, patient withdrawal, investigator decision, or death. Main outcomes and measures: The primary end point was 12-month progression-free survival (PFS) rate (according to Response Evaluation Criteria in Solid Tumours, version 1.1 criteria); PFS was defined as the time from enrollment to disease progression or death. Adverse events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results: A total of 307 patients were assessed for trial eligibility, of whom 266 were ineligible for enrollment. Of the 41 patients enrolled, 3 did not fulfill all inclusion criteria and were excluded. The remaining 38 patients (28 [73.7%] male; mean [SD] age, 63.7 [8.3] years) constituted the per-protocol population. The 12-month PFS rate was 51.3% (95% CI, 34.2%-66.0%), which met the primary end point. The 12-month overall survival (OS) rate was 72.0% (95% CI, 54.1%-83.9%). The median PFS was 13.0 months (95% CI, 7.9-18.0 months), and the median OS was not reached. Of the 38 patients, 16 (42.1%) achieved an objective response and 30 (78.9%) achieved disease control. The median time to response was 2.8 months (IQR, 2.8-3.58 months), with a median duration of response of 11.7 months (range, 3.57-22.4 months; the response was ongoing at cutoff). Of 16 responses, 8 (50.0%) were ongoing. Most adverse events were grade 1 or 2. For atezolizumab, the most common adverse events were fatigue (6 [15.8%]) and pruritus (6 [15.8%]). For bevacizumab, they were hypertension (10 [26.3%]) and proteinuria (4 [10.5%]). Drug discontinuation occurred in 2 patients receiving atezolizumab (5.3%) and 3 patients receiving bevacizumab (7.9%). PD-L1 levels were not associated with response, PFS, or OS. Conclusions and relevance: These findings suggest that atezolizumab with bevacizumab is a potential treatment for high-TMB nonsquamous NSCLC

Microsatellite alterations and TP53 mutations in plasma DNA of small-cell lung cancer patients: Follow-up study and prognostic significance

Background: Small-cell lung cancer (SCLC), one of the major types of lung cancer, is associated with many different somatic molecular genetic changes. These alterations, observed in tumor DNA, have also been identified in the plasma DNA of patients. We undertook the present study to make a prospective investigation into the correlation between abnormal plasma DNA and patient survival. Patients and methods: Thirty-five patients with SCLC were selected after histological diagnosis. Polymorphic markers (ACTBP2, UT762 and AR) were chosen for their reported high rate of alterations in SCLC and analyzed in tumor tissue, normal blood cells and plasma DNA. Furthermore, we looked for mutations of the TP53 gene in tumor and plasma DNA. Results: In 25 patients (71%) at least one molecular change precisely matching that of the primary tumor was detected in the plasma DNA. No difference in survival was observed between patients with aberrant plasma DNA and patients without plasma DNA alterations. However, patients with microsatellite modifications and TP53 mutations concomitantly, showed a significant difference (P = 0.02) in survival compared with patients bearing only one of these molecular changes. In 15 cases it was possible to find a correlation either between tumor response and disappearance of abnormal plasma DNA, or tumor progression and persistence of plasma DNA alterations. Conclusions: Free plasma DNA with molecular alterations is present to a high degree in plasma DNA of SCLC patients and may have a role as a prognostic facto

Mutational status of K- ras and TP53 genes in primary sarcomas of the heart

We investigated three patients with cardiac angiosarcomas and two with cardiac rhabdomyosarcomas, all for mutations at exons 5, 6, 7 and 8 of the p53 gene and at exon 1 of K- ras. No point mutations were observed in the p53 gene in any of the five cases; however, at exon 1 of K- ras, three patients (60%) presented the same mutation at the first base of codon 13 (G to A transition). Interestingly, this mutation was detected in both rhabdomyosarcoma and angiosarcoma histologic sarcoma types. © 2000 Cancer Research Campaig

SEOM clinical guidelines for the treatment of non‑small cell lung cancer (2018)

Non-small cell lung cancer (NSCLC) accounts for up to 85% of all lung cancers. The last few years have seen the development of a new staging system, diagnostic procedures such as liquid biopsy, treatments like immunotherapy, as well as deeper molecular knowledge; so, more options can be offered to patients with driver mutations. Groups with specific treatments account for around 25% and demonstrate significant increases in overall survival, and in some subgroups, it is important to evaluate each treatment alternative in accordance with scientific evidence, and even more so with immunotherapy. New treatments similarly mean that we must reconsider what should be done in oligometastatic disease where local treatment attains greater valu

Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non–Small-Cell Lung Cancer (NADIM phase II trial)

PURPOSE Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non–small cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3- year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival

Low-dislocation-density GaN from a single growth on a textured substrate

The density of threading dislocations (TD) in GaN grown directly on flat sapphire substrates is typically greater than 10{sup 9}/cm{sup 2}. Such high dislocation densities degrade both the electronic and photonic properties of the material. The density of dislocations can be decreased by orders of magnitude using cantilever epitaxy (CE), which employs prepatterned sapphire substrates to provide reduced-dimension mesa regions for nucleation and etched trenches between them for suspended lateral growth of GaN or AlGaN. The substrate is prepatterned with narrow lines and etched to a depth that permits coalescence of laterally growing III-N nucleated on the mesa surfaces before vertical growth fills the etched trench. Low dislocation densities typical of epitaxial lateral overgrowth (ELO) are obtained in the cantilever regions and the TD density is also reduced up to 1 micrometer from the edge of the support regions

SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019)

Small-cell lung cancer (SCLC) accounts for 15% of lung cancers. Only one-third of patients are diagnosed at limited stage. The median survival remains to be around 15-20 months without significative changes in the strategies of treatment for many years. In stage I and IIA, the standard treatment is the surgery followed by adjuvant therapy with platinum-etoposide. In stage IIB-IIIC, the recommended treatment is early concurrent chemotherapy with platinum-etoposide plus thoracic radiotherapy followed by prophylactic cranial irradiation in patients without progression. However, in the extensive stage, significant advances have been observed adding immunotherapy to platinum-etoposide chemotherapy to obtain a significant increase in overall survival, constituting the new recommended standard of care. In the second-line treatment, topotecan remains as the standard treatment. Reinduction with platinum-etoposide is the recommended regimen in patients with sensitive relapse (≥ 3 months) and new drugs such as lurbinectedin and immunotherapy are new treatment options. New biomarkers and new clinical trials designed according to the new classification of SCLC subtypes defined by distinct gene expression profiles are necessary