Transient Reversal of Episome Silencing Precedes VP16-Dependent Transcription during Reactivation of Latent HSV-1 in Neurons

Herpes simplex virus type-1 (HSV-1) establishes latency in peripheral neurons, creating a permanent source of recurrent infections. The latent genome is assembled into chromatin and lytic cycle genes are silenced. Processes that orchestrate reentry into productive replication (reactivation) remain poorly understood. We have used latently infected cultures of primary superior cervical ganglion (SCG) sympathetic neurons to profile viral gene expression following a defined reactivation stimulus. Lytic genes are transcribed in two distinct phases, differing in their reliance on protein synthesis, viral DNA replication and the essential initiator protein VP16. The first phase does not require viral proteins and has the appearance of a transient, widespread de-repression of the previously silent lytic genes. This allows synthesis of viral regulatory proteins including VP16, which accumulate in the cytoplasm of the host neuron. During the second phase, VP16 and its cellular cofactor HCF-1, which is also predominantly cytoplasmic, concentrate in the nucleus where they assemble an activator complex on viral promoters. The transactivation function supplied by VP16 promotes increased viral lytic gene transcription leading to the onset of genome amplification and the production of infectious viral particles. Thus regulated localization of de novo synthesized VP16 is likely to be a critical determinant of HSV-1 reactivation in sympathetic neurons

Gene activation is required for developmentally programmed cell death.

The intersegmental muscles of the tobacco hawkmoth Manduca sexta die during the 36-hr period after metamorphosis. The trigger for cell death is a fall in the ecdysteroid titer. Commitment of the intersegmental muscles to degenerate involves selective repression and activation of ecdysteroid-responsive genes. When the pattern of gene expression is altered after injection of either 20-hydroxyecdysone or actinomycin D, the muscles persist. cDNA clones have been isolated for four genes that become abundantly expressed coincident with the commitment to degenerate. The data presented here indicate that programmed cell death is not due to the cessation of macromolecular synthesis in condemned cells but rather is due to the activation of a differentiative pathway

HER2-positive breast cancer -a vailable anti-HER2 therapies and new agents under investigation

Introduction and objectives. Breast cancer (BC) is the most common malignancy and the leading cause of cancer death among women. About 15–20% of all BCs are HER2-positive. Proper assessment of HER2 status is crucial to choose appropriate treatment. The review summarizes data on anti-HER2 drugs used to treat HER2-positive BC and provides basic information on new agents under investigation. Brief description of the state of knowledge. Specific HER2-targeting drugs are available or are being evaluated in clinical trials. Anti-HER2 agents include: monoclonal antibodies, tyrosine kinase inhibitors, antibody-drug conjugates, bispecific antibodies, PI3K/AKT/mTOR inhibitors and heat shock protein 90 inhibitors, HER2-targeting vaccines and CDK4/6 inhibitors. The advent of anti-HER2 therapies increased the time of progression free survival and overall survival in BC patients. Results. Final analysis of the CLEOPATRA trial shows that the combination of trastuzumab, pertuzumab and taxane significantly improved outcomes in metastatic HER2-positive BC and it is currently preferred first-line treatment. The recommended second-line treatment is based on trastuzumab emtansine or on the combination of lapatinib and capecitabine. Some promising agents such as margetuximab or trastuzumab deruxtecan are still under investigation. Conclusions. Anti-HER2 directed treatment undoubtedly improves outcomes among patients with HER2-positive BC. Access to drugs such as trastuzumab, pertuzumab, lapatinib and T-DM1 improves prognosis even in patients with advanced disease. Further studies and clinical trials on novel anti-HER2 therapies are required. Nevertheless, BC treatment is becoming more effective and, hopefully, one day it may be possible to cure patients even with metastases

High-risk HPV test in cervical cancer prevention - present and future

Introduction. Cervical cancer is the fourth most common cancer among women. It is related to persistent HPV infection. In order to improve diagnostic methods, a lot of research has been focused on detecting HPV DNA. A test known as a high- risk HPV test or HPV primary screening provides very encouraging results. Objective.The aim of this review is to present the actual knowledge about the possibilities of cervical cancer screening methods. Particular attention is paid to the question concerning the effectiveness of detecting viral DNA as a screening programme, compared to pap smear. State of knowledge. The HPV primary screening has higher sensitivity than the cervical smear test and it is able to detect lower-stage lesions, which are considered clinically irrelevant. Nonetheless, many HPV infections recede naturally. Therefore, relying only on the results of this test may expose women to unnecessary colposcopies and stress. Due to this fact, women under 30 years should not be screened with the hrHPV test. In view of its limitations, the HPV primary screening strategy is still tested worldwide as a pilot project. In Poland in 2019, a pilot project with the hrHPV test started at the National Institute of Oncology. Conclusions. Detecting viral DNA has its advantages and disadvantages. Further research is still required, but the hrHPV test has a great opportunity to become one of the main screening programmes worldwide, or at least, a valuable addition to cervical smear test