Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword

Major currently used anticancer therapeutics either directly damage DNA or target and upset basic cell division mechanisms like DNA replication and chromosome segregation. These insults elicit activation of cell cycle checkpoints, safeguard mechanisms that cells implement to correctly complete cell cycle phases, repair damage or eventually commit suicide in case damage is unrepairable. Although cancer cells appear to be advantageously defective in some aspects of checkpoint physiology, recent acquisitions on the biochemical mechanisms of the various checkpoints are offering new therapeutic approaches against cancer. Indeed, chemical manipulation of these mechanisms is providing new therapeutic strategies and tools to increase the killing efficacy of major cancer therapeutics as well as to directly promote cancer cell death. In this review we summarize developing concepts on how targeting cell cycle checkpoints may provide substantial improvement to cancer therapy

Invasione di specie aliene: comparsa di Polyphemus pediculus (Linnaeus, 1761; Crustacea Cladocera) nel Lago Maggiore

Polyphemus pediculus (Linnaeus, 1761) is a holoarctic cladoceran species typically inhabiting the littoral zone of lakes. It is a voracious predator, hunting its prey by visual predation, able to deplete the zooplankton population. Its detection for the first time in Lake Maggiore, at a sampling station close to the littoral, in which zooplankton was monitored for 20 years is worth of being discussed. First, because it represents a further increase in predatory Cladocera, after Bythotrephes longimanus (Leydig, 1860) have successfully re-emerged in the open water. Second, because it may be regarded as an increasing invasion trend in a lake traditionally considered as a stable, mature environment, in which invasions should be hardly successful.Polyphemus pediculus (Linnaeus, 1761) ? un cladocero oloartico che tipicamente colonizza la zona litorale dei laghi. ? un predatore vorace, che attua una strategia di predazione visiva, in grado di decimare il popolamento zooplanctonico. La presenza di questo organismo, rilevata per la prima volta in campioni provenienti da una stazione del Lago Maggiore, posta vicino alla zona litorale nella quale lo zooplancton viene monitorato da 20 anni, ? meritevole di discussione. Primo, perch? rappresenta un ulteriore aumento della frazione di Cladoceri predatori, dopo l\u27accresciuta presenza numerica di Bythotrephes longimanus (Leydig, 1860) nelle acque pelagiche. Secondo, perch? pu? essere considerato un aumento della tendenza alle invasioni, in un lago tradizionalmente considerato come un ambiente stabile e maturo, nel quale pertanto la probabilit? di successo delle invasioni dovrebbe essere bassa

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

Glioblastomas are the most frequent and malignant brain tumor hallmarked by an invariably poor prognosis. They have been classically differentiated into primary isocitrate dehydrogenase 1 or 2 (IDH1 -2) wild-type (wt) glioblastoma (GBM) and secondary IDH mutant GBM, with IDH wt GBMs being commonly associated with older age and poor prognosis. Recently, genetic analyses have been integrated with epigenetic investigations, strongly implementing typing and subtyping of brain tumors, including GBMs, and leading to the new WHO 2021 classification. GBM genomic and epigenomic profile influences evolution, resistance, and therapeutic responses. However, differently from other tumors, there is a wide gap between the refined GBM profiling and the limited therapeutic opportunities. In addition, the different oncogenes and tumor suppressor genes involved in glial cell transformation, the heterogeneous nature of cancer, and the restricted access of drugs due to the blood–brain barrier have limited clinical advancements. This review will summarize the more relevant genetic alterations found in GBMs and highlight their potential role as potential therapeutic targets

The Platelet-derived Growth Factor Controls c-myc Expression through a JNK- and AP-1-dependent Signaling Pathway *

Pro-inflammatory cytokines, environmental stresses, as well as receptor tyrosine kinases regulate the activity of JNK. In turn, JNK phosphorylates Jun members of the AP-1 family of transcription factors, thereby controlling processes as different as cell growth, differentiation, and apoptosis. Still, very few targets of the JNK-Jun pathway have been identified. Here we show that JNK is required for the induction of c-myc expression by PDGF. Furthermore, we identify a phylogenetically conserved AP-1-responsive element in the promoter of the c-myc proto-oncogene that recruits in vivo the c-Jun and JunD AP-1 family members and controls the PDGF-dependent transactivation of the c-myc promoter. These findings suggest the existence of a novel biochemical route linking tyrosine kinase receptors, such as those for PDGF, and c-myc expression through JNK activation of AP-1 transcription factors. They also provide a novel potential mechanism by which both JNK and Jun proteins may exert either their proliferative or apoptotic potential by stimulating the expression of the c-myc proto-oncogene

Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis

OBJECTIVE: Intrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS). Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS. METHODS: We combined new proteomic method, TRIDENT, CSF analysis, and advanced 3T magnetic resonance imaging (MRI), in 64 MS patients at the time of diagnosis and 26 controls with other neurological disorders. MS patients were stratified according to cortical lesion (CL) load. RESULTS: We identified 227 proteins differently expressed between the patients with high and low CL load. These were mainly related to complement and coagulation cascade as well as to iron homeostasis pathway (30 and 6% of all identified proteins, respectively). Accordingly, in the CSF of MS patients with high CL load at diagnosis, significantly higher levels of sCD163 (P < 0.0001), free hemoglobin (Hb) (P < 0.05), haptoglobin (P < 0.0001), and fibrinogen (P < 0.01) were detected. By contrast, CSF levels of sCD14 were significantly (P < 0.05) higher in MS patients with low CL load. Furthermore, CSF levels of sCD163 positively correlated (P < 0.01) with CSF levels of neurofilament, fibrinogen, and B cell-related molecules, such as CXCL13, CXCL12, IL10, and BAFF. INTERPRETATION: Intrathecal dysregulation of iron homeostasis and coagulation pathway as well as B-cell and monocyte activity are strictly correlated with cortical damage at early disease stages

Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Cav3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background

Indagini limnologiche nell\u27area antistante la foce del Torrente San Bernardino (sopralluogo del 14 giugno 2010)

No abstract availabl

Acquired atresia of the external auditory canal and canaloplasty with Thiersch graft reconstruction: Outcomes and complications

Acquired atresia of the external auditory canal (EAC) is a rare disease characterized by otorrhea and progressive hearing loss. Clinically, it is differentiated into two stages: the wet stage and the dry stage. The dry stage does not respond to pharmacological treatment and has to be treated surgically. One surgical option is canaloplasty of the EAC with Thiersch graft reconstruction. This study aimed to report the follow-up outcomes (otomicroscopic signs and pure tone audiometry [PTA]) in patients with acquired atresia treated with this technique. Eighteen adult patients surgically treated for acquired atresia of the EAC between 2010 and 2020 were enrolled. All underwent canaloplasty with Thiersch graft reconstruction by one senior surgeon. Otomicroscopy and PTA results were evaluated before and after surgery. Postsurgical follow-up was performed at 1-3-6-12 months and then annually. Presurgical otomicroscopic examination revealed stenosis that occluded more than 75% of the EAC in all patients, and preoperative PTA showed conductive hearing loss in 89% of patients. However, postsurgical otomicroscopic examination showed that 94% of patients had a normal EAC diameter after one year, and only one patient had anterior blunting and recurrent atresia. In addition, postsurgical PTA evidenced a normal range in 89% of patients after one year. In conclusion, acquired atresia of the EAC is a troublesome disease usually associated with hearing loss. Therefore, treatment is chosen to resolve its symptoms. The results demonstrate evidence that canaloplasty with Thirsch graft may be a suitable surgical method considering the lower incidence of recurrence and the excellent hearing outcomes