Since the COVID-19 pandemic alarm was made by the severe acute respiratory syndrome (SARS)-coronavirus (CoV) 2, several institutions and agencies have pursued to clarify the viral virulence and ...infectivity. The fast propagation of this virus leads to an unprecedented rise in the number of cases worldwide. COVID-19 virus is exceptionally contagious that spreads through droplets, respiratory secretions, and direct contact. The enveloped, single-stranded RNA virus has a specific envelop region called (S) region encoding (S protein) that specifically binds to the host cell receptor. Viral infection requires receptors' participation on the host cell membrane's surface, a key- step for the viral invasion of susceptible cells. Recently, the Italian alpha 1 antitrypsin Registry results showed a close geographic distribution of positive cases like the one recorded for SARS -CoV-2 infection. AAT deficient patients presented with the highest infection rates. They were giving attention to alpha 1 antitrypsin AAT's role in COVID-19 infection. Alpha 1 antitrypsin deficiency (AATD) is undoubtedly the most common genetic condition in adults. AATD is characterized by decreased serum levels or impaired AAT action, raising the risk of developing many diseases, particularly pulmonary emphysema cirrhosis of the liver. This review will discuss the main immunological properties that AAT has as a protective agent against the infection and possible therapeutic application.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL oncoprotein, known to drive leukemogenesis by orchestrating multiple signaling pathways ultimately ...involved in cell survival. Despite successful response rates of CML patients to tyrosine kinase inhibitors (TKIs), resistance eventually arises due to BCR-ABL-dependent and independent mechanisms. Survivin is an inhibitor of apoptosis protein acting in the interface between apoptosis deregulation and cell cycle progression. In CML, high levels of survivin have been associated with late stages of disease and therapy resistance. In this review, we provide an overview of important aspects concerning survivin subcellular localization and expression pattern in CML patients and cell lines. Moreover, we highlight the relevance of molecular networks involving survivin for disease progression and treatment resistance. Finally, we discuss the mechanisms accounting for survivin overexpression, as well as novel therapeutic interventions that have been designed to counteract survivin-associated malignancy in CML.
Fibroblast Growth Factor (FGF) ligands and their receptors are crucial factors driving chemoresistance in several malignancies, challenging the efficacy of currently available anti-cancer drugs. The ...Fibroblast growth factor/receptor (FGF/FGFR) signalling malfunctions in tumor cells, resulting in a range of molecular pathways that may impact its drug effectiveness. Deregulation of cell signalling is critical since it can enhance tumor growth and metastasis. Overexpression and mutation of FGF/FGFR induce regulatory changes in the signalling pathways. Chromosomal translocation facilitating FGFR fusion production aggravates drug resistance. Apoptosis is inhibited by FGFR-activated signalling pathways, reducing multiple anti-cancer medications' destructive impacts. Angiogenesis and epithelial-mesenchymal transition (EMT) are facilitated by FGFRs-dependent signalling, which correlates with drug resistance and enhances metastasis. Further, lysosome-mediated drug sequestration is another prominent method of resistance. Inhibition of FGF/FGFR by following a plethora of therapeutic approaches such as covalent and multitarget inhibitors, ligand traps, monoclonal antibodies, recombinant FGFs, combination therapy, and targeting lysosomes and micro RNAs would be helpful. As a result, FGF/FGFR suppression treatment options are evolving nowadays. To increase positive impacts, the processes underpinning the FGF/FGFR axis' role in developing drug resistance need to be clarified, emphasizing the need for more studies to develop novel therapeutic options to address this significant problem.
Communicated by Ramaswamy H. Sarma
•Parkin and DAT have been independently associated with Parkinson’s Disease.•The associations of parkin and DAT in PD have not been established.•There is a significant overlap of molecules between ...the DAT and Parkin pathways.•Conceivable interaction between the pathways can be identified.•Neurons from iPSC can be used as a model to study parkin and DAT associations.
Parkinson’s disease (PD) is a neurodegenerative disorder accompanied by depletion of dopamine(DA) and loss of dopaminergic (DAergic) neurons in the brain that is believed to be responsible for the motor and non-motor symptoms of PD. Dopamine Transporter (DAT) is essential for reuptake of DA into the presynaptic terminal, thereby controlling the availability and spatial activity of released DA. Parkin interacts with proteins involved in the endosomal pathway, suggesting that presynaptic Parkin could regulate the expression of DAT in the plasma membrane. Parkin mutations lead to early synaptic damage and it appears as a crucial gene having a vast functioning area. PD-specific induced pluripotent stem cells (iPSCs) derived DA neurons exist as a potential tool for in-vitro modeling of PD, as they can recapitulate the pathological features of PD. The exact mechanism of PARKIN influenced DAT variations and changes in DA reuptake by DAT remain unknown. Hence, DAT and PARKIN mutated PD-specific iPSCs-derived DA neurons could provide important clues for elucidating the pathogenesis and mechanism of PD. This mysterious and hidden connection may prove to be a boon in disguise, hence, here we review the influence of PARKIN and DAT on DA mechanism and will discuss how these findings underpin the concept of how downregulation or upregulation of DAT is influenced by PARKIN. We conclude that the establishment of new model for PD with a combination of DAT and PARKIN would have a high translational potential, which includes the identification of drug targets and testing of known and novel therapeutic agents.
Highlights • SMA has evolving phenotypes due to improved standard of care and new treatments • The clinician should be alert to identify new patterns of motor development in SMA • Other organ systems ...may develop signs of dysfunction as these patients live longer • Early diagnosis, including newborn screening, warrants consideration • Strategies targeting the CNS and peripheral tissues are warrant consideration
The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is ...characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines—blocking transmission and antiviral therapy—inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother‐to‐child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.
Over the past decade, there has been an explosion of interest in clinical applications of attachment theory. In the present article, we briefly describe John Bowlby's model of therapeutic change, the ...therapeutic relationship, and the therapist's role in emotional healing. We then review empirical evidence for three key propositions in Bowlby's model. First, a client's sense of security during therapy is crucial for facilitating therapeutic work. Second, a therapist's own sense of security contributes to positive therapeutic outcomes. Third, attachment insecurities can be effectively reduced in therapy, and movement toward greater attachment security is central to achieving favorable therapeutic outcomes. In sum, research evidence confirms the importance of establishing what Bowlby called a safe haven and a secure base within a therapeutic relationship.
Glioblastoma (GB) is an intrusive and recurrent primary brain tumor with low survivability. The heterogeneity of the tumor microenvironment plays a crucial role in the stemness and proliferation of ...GB. The tumor microenvironment induces tumor heterogeneity of cancer cells by facilitating clonal evolution and promoting multidrug resistance, leading to cancer cell progression and metastasis. It also plays an important role in angiogenesis to nourish the hypoxic tumor environment. There is a strong interaction of neoplastic cells with their surrounding microenvironment that comprise several immune and non-immune cellular components. The tumor microenvironment is a complex network of immune components like microglia, macrophages, T cells, B cells, natural killer (NK) cells, dendritic cells and myeloid-derived suppressor cells, and non-immune components such as extracellular matrix, endothelial cells, astrocytes and neurons. The prognosis of GB is thus challenging, making it a difficult target for therapeutic interventions. The current therapeutic approaches target these regulators of tumor micro-environment through both generalized and personalized approaches. The review provides a summary of important milestones in GB research, factors regulating tumor microenvironment and promoting angiogenesis and potential therapeutic agents widely used for the treatment of GB patients.
Moderate to severe traumatic brain injury causes significant cognitive impairments, including impairments in social cognition, the ability to recognize others' emotions, and infer others' thoughts. ...These cognitive impairments can have profound negative effects on communication functions, resulting in a cognitive-communication disorder. Cognitive-communication disorders can significantly limit a person's ability to socialize, work, and study, and thus are critical targets for intervention. This article presents the updated INCOG 2.0 recommendations for management of cognitive-communication disorders. As social cognition is central to cognitive-communication disorders, this update includes interventions for social cognition.
An expert panel of clinicians/researchers reviewed evidence published since 2014 and developed updated recommendations for interventions for cognitive-communication and social cognition disorders, a decision-making algorithm tool, and an audit tool for review of clinical practice.
Since INCOG 2014, there has been significant growth in cognitive-communication interventions and emergence of social cognition rehabilitation research. INCOG 2.0 has 9 recommendations, including 5 updated INCOG 2014 recommendations, and 4 new recommendations addressing cultural competence training, group interventions, telerehabilitation, and management of social cognition disorders. Cognitive-communication disorders should be individualized, goal- and outcome-oriented, and appropriate to the context in which the person lives and incorporate social communication and communication partner training. Group therapy and telerehabilitation are recommended to improve social communication. Augmentative and alternative communication (AAC) should be offered to the person with severe communication disability and their communication partners should also be trained to interact using AAC. Social cognition should be assessed and treated, with a focus on personally relevant contexts and outcomes.
The INCOG 2.0 recommendations reflect new evidence for treatment of cognitive-communication disorders, particularly social interactions, communication partner training, group treatments to improve social communication, and telehealth delivery. Evidence is emerging for the rehabilitation of social cognition; however, the impact on participation outcomes needs further research.
CAFs have dual roles in cancer because they can exert both tumor-promoting and tumor-suppressing effects, likely owing to their heterogeneity and plasticity.Senescent fibroblasts can influence PDAC ...pathophysiology and patient outcome through their senescence-associated secretory phenotype (SASP).The secretome of activated PSCs (aPSCs) and CAFs modulates and is modulated by tumor and stromal cells, thus creating a highly complex and intricate crosstalk.Fibroblast-derived extracellular vesicles (EVs) can sustain oncogenic signaling in PDAC cells and directly fuel them by transporting miRNAs, long non-coding RNAs (lncRNAs), proteins, mRNAs, lipids, and metabolites.Stroma-targeted therapies may lead to opposite outcomes. Fibroblast reprogramming appears to be a promising strategy.aPSCs/CAFs and their respective EVs provide a source of biomarkers for diagnosis, prognosis, and drug response, as well as information about CAF expression at a particular timepoint.
Pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) are highly abundant cells in the pancreatic tumor microenvironment (TME) that modulate desmoplasia. The formation of a dense stroma leads to immunosuppression and therapy resistance that are major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that several subpopulations of CAFs in the TME can interconvert, explaining the dual roles (antitumorigenic and protumorigenic) of CAFs in PDAC and the contradictory results of CAF-targeted therapies in clinical trials. This highlights the need to clarify CAF heterogeneity and their interactions with PDAC cells. This review focuses on the communication between activated PSCs/CAFs and PDAC cells, as well as on the mechanisms underlying this crosstalk. CAF-focused therapies and emerging biomarkers are also outlined.
PDF
