Notch signaling deregulation in multiple myeloma: A rational molecular target

Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches.     

Cerebral involvement in COVID-19 is associated with metabolic and coagulation derangements: an EEG study

Journal of Neurology -     

Serum phosphorylated neurofilament heavy-chain levels reflect phenotypic heterogeneity and are an independent predictor of survival in motor neuron disease

Journal of Neurology - To investigate the prognostic role and the major determinants of serum phosphorylated neurofilament heavy -chain (pNfH) concentration across a large cohort of motor neuron...     

Unpleasant Bodily Odour in a Psychoanalytic Treatment: Bridge or Drawbridge to a Troubled Past?

In this paper, I explore the topic of primitive bodily communications and countertransference enactments, with a particular focus on the part played by bodily odour. To explore this topic, I discuss a two-year treatment with a patient who presented with a mix of borderline and narcissistic diagnostic features. I describe meaningful aspects of the difficulties faced in countertransference work when receiving and making sense of the patient's use of primitive defences and I highlight their expression through a very uncomfortable symptom: an extremely unpleasant bodily smell. My thesis is that the smell communicated preverbal and unsymbolized experiences of early physical and emotional neglect, as well as evacuating the toxicity of those experiences. In this way the smell acted both as a bridge, which could help me reconstruct my patient's early traumatic past, and as a drawbridge, to keep me at distance and maintain his past dissociated. The invasive and aversive nature of the smell can also be seen as representing the approach-avoidance dilemma typical of a disorganized attachment state of mind, acting both as a bridge and as a drawbridge to attachment and relating.     

Combined use of cytology,p16 immunostaining and genotyping for triage of women positive for high-risk human papillomavirus at primary screening

Human papillomavirus (HPV) testing is very sensitive for primary cervical screening but has low specificity. Triage tests that improve specificity but maintain high sensitivity are needed. Women enrolled in the experimental arm of Phase 2 of the New Technologies for Cervical Cancer randomized controlled cervical screening trial were tested for high-risk HPV (hrHPV) and referred to colposcopy if positive. hrHPV-positive women also had HPV genotyping (by polymerase chain reaction with GP5+/GP6+ primers and reverse line blotting), immunostaining for p16 overexpression and cytology. We computed sensitivity, specificity and positive predictive value (PPV) for different combinations of tests and determined potential hierarchical ordering of triage tests. A number of 1,091 HPV-positive women had valid tests for cytology, p16 and genotyping. Ninety-two of them had cervical intraepithelial neoplasia grade 2+ (CIN2+) histology and 40 of them had CIN grade 3+ (CIN3+) histology. The PPV for CIN2+ was >10% in hrHPV-positive women with positive high-grade squamous intraepithelial lesion (61.3%), positive low-grade squamous intraepithelial lesion (LSIL+) (18.3%) and positive atypical squamous cells of undetermined significance (14.8%) cytology, p16 positive (16.7%) and, hierarchically, for infections by HPV33, 16, 35, 59, 31 and 52 (in decreasing order). Referral of women positive for either p16 or LSIL+ cytology had 97.8% sensitivity for CIN2+ and women negative for both of these had a 3-year CIN3+ risk of 0.2%. Similar results were seen for women being either p16 or HPV16/33 positive. hrHPV-positive women who were negative for p16 and cytology (LSIL threshold) had a very low CIN3+ rate in the following 3 years. Recalling them after that interval and referring those positive for either test to immediate colposcopy seem to be an efficient triage strategy. The same applies to p16 and HPV16.     

Role of microRNAs in host defense against Echinococcus granulosus infection: a preliminary assessment

Immunologic Research - Cystic echinococcosis (CE) is a neglected helminthic zoonosis caused by the larval stage of the tapeworm Echinococcus granulosus s.l. MicroRNAs (miRNAs) are regulators of...