Outcomes of patients with non-small cell lung cancer and poor performance status treated with immune checkpoint inhibitors in the real-world setting

International Journal of Clinical Oncology - Immune-checkpoint inhibitors (ICIs) are standard treatments for metastatic non-small cell lung cancer (NSCLC). Patients with poor performance status...     

In the Era of mRNA Vaccines,Is There Any Hope for HIV Functional Cure?

Over 36 million people worldwide are infected with HIV. Antiretroviral therapy (ART) has proven to be highly effective to prevent HIV-1 transmission, clinical progression and death. Despite this success, the number of HIV-1 infected individuals continues increasing and ART should be taken for life. Therefore, there are two main priorities: the development of preventive vaccines to protect from HIV acquisition and achieve an efficient control of HIV infection in the absence of ART (functional cure). In this sense, in the last few years, there has been a broad interest in new and innovative approaches such as mRNA-based vaccines. RNA-based immunogens represent a promising alternative to conventional vaccines because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. Some mRNA-based vaccines platforms against infectious diseases have demonstrated encouraging results in animal models and humans. However, their application is still limited because the instability and inefficient in vivo delivery of mRNA. Immunogens, design, immunogenicity, chemical modifications on the molecule or the vaccine delivery methods are all crucial interventions for improvement. In this review we, will present the current knowledge and challenges in this research field. mRNA vaccines hold great promises as part of a combined strategy, for achieving HIV functional cure.     

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

The αvβ6 integrin plays a role in compromised epidermal wound healing

The alphavbeta6 integrin is an exclusively epithelial integrin that is highly expressed during fetal development. In adult tissue, alphavbeta6 integrin is expressed during inflammation, carcinogenesis, and in wound healing. We previously reported that alphavbeta6 integrin is highly expressed in poorly healing human wounds and its over-expression is associated with chronic wounds in a mouse model. The objective of this study was to investigate the role of alphavbeta6 integrin in compromised wound healing induced by hydrocortisone treatment or aging by using young and old mice deficient in or overexpressing the beta6 integrin subunit in the epidermis. Untreated aged beta6 integrin-deficient (beta6-/-) animals showed a significant delay in wound healing when compared to their age-matched controls or younger beta6-/- mice. The most significant delay was observed at the stages where granulation tissue deposition was occurring. Hydrocortisone treatment significantly delayed wound healing in wild-type and beta6 integrin-deficient mice in comparison with the untreated controls. However, hydrocortisone treatment in beta6 integrin overexpressing animals did not cause a significant delay in wound healing. The results of this study suggest that alphavbeta6 integrin plays an important role in wound healing in animals compromised by either age or stress mimicked by hydrocortisone.     

Moisturizing effect of cosmetic formulations containing Aloe vera extract in different concentrations assessed by skin bioengineering techniques

BACKGROUND/PURPOSE: The polysaccharide-rich composition of Aloe vera extracts (Aloe barbadensis Miller), often used in cosmetic formulations, may impart moisturizing properties to the product. The aim of this study was to evaluate the effect of cosmetic formulations containing different concentrations of freeze-dried Aloe vera extract on skin hydration, after a single and a 1- and 2-week period of application, by using skin bioengineering techniques. METHODS: Stable formulations containing 5% (w/w) of a trilaureth-4 phosphate-based blend were supplemented with 0.10%, 0.25% or 0.50% (w/w) of freeze-dried Aloe vera extract and applied to the volar forearm of 20 female subjects. Skin conditions in terms of the water content of the stratum corneum and of transepidermal water loss (TEWL) (Corneometer CM 825 and Tewameter TM 210) were analysed before and after a single and 1- and 2-week period of daily application. RESULTS: After a single application, only formulations supplemented with 0.25% and 0.50% (w/w) of Aloe vera extract increased the water content of the stratum corneum, while after the 2-week period application, all formulations containing the extract (0.10%, 0.25% and 0.50%) had the same effect, in both cases as compared with the vehicle. TEWL was not modified after a single and after 1- and 2-week period of application, when compared with the vehicle. CONCLUSION: Our results show that freeze-dried Aloe vera extract is a natural effective ingredient for improving skin hydration, possibly through a humectant mechanism. Consequently, it may be used in moisturizing cosmetic formulations and also as a complement in the treatment of dry skin.     

Frontal white matter volume and delta EEG sources negatively correlate in awake subjects with mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: A relationship between brain atrophy and delta rhythmicity (1.5-4 Hz) has been previously explored in Alzheimer's disease (AD) subjects [Fernandez A, Arrazola J, Maestu F, Amo C, Gil-Gregorio P, Wienbruch C, Ortiz T. Correlations of hippocampal atrophy and focal low-frequency magnetic activity in Alzheimer disease: volumetric MR imaging-magnetoencephalographic study. Am J Neuroradiol. 2003 24(3):481-487]. In this study, we tested the hypothesis that such a relationship does exist not only in AD patients but also across the continuum of subjects with mild cognitive impairment (MCI) and AD. METHODS: Resting, eyes-closed EEG data were recorded in 34 MCI and 65 AD subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by LORETA. Cortical EEG sources were correlated with MR-based measurements of lobar brain volume (white and gray matter). RESULTS: A negative correlation was observed between the frontal white matter and the amplitude of frontal delta sources (2-4 Hz) across MCI and AD subjects. CONCLUSIONS: These results confirmed for the first time the hypothesis that the sources of resting delta rhythms (2-4 Hz) are correlated with lobar brain volume across MCI and AD subjects. SIGNIFICANCE: The present findings support, at least at group level, the 'transition hypothesis' of brain structural and functional continuity between MCI and AD.     

Different patterns of 11q allelic losses in digestive endocrine tumors

Most foregut digestive endocrine neoplasms may be associated with the multiple endocrine type 1 (MEN-1) syndrome. In contrast, midgut/hindgut carcinoids never show such association. To investigate the pathogenetic involvement of the MEN-1 gene and of putative additional oncosuppressor gene(s) distal to it, a comparative analysis of loss of heterozygosity (LOH) at chromosome 11q13 to 11qter was performed in 27 foregut (pancreatic endocrine tumors [PETs]), 23 midgut (ileal and appendiceal), and 3 hindgut (rectal) endocrine tumors. LOH at the MEN-1 gene locus at 11q13 was observed in 52% of the 23 sporadic and in all 4 MEN-1-associated PETs and was found to consistently and continuously span to the most distal marker investigated at 11qter. In contrast, only occasional, discontinuous, and mostly interstitial LOH for 11q markers was observed in ileal (midgut) carcinoids, whereas no LOH was found in all appendiceal (midgut) and rectal (hindgut) carcinoids. The consistent extension of LOH from the MEN-1 region to 11qter in sporadic PETs suggests a mechanism of gene inactivation via chromosomal breakage and complete loss of chromosome 11q; furthermore, these results expand beyond the 11q13 region the search for additional oncosuppressor gene(s) potentially involved in the genesis of these neoplasms. The low frequency, limited extension, and discontinuous distribution of 11q deletions in midgut/hindgut carcinoids suggest that MEN-1 gene is not involved in the pathogenesis of these tumors.     

Most human isolates of Mycobacterium avium Mav-A and Mav-B are strong producers of hemolysin, a putative virulence factor

Hemolysin was quantified in 58 isolates of Mycobacterium avium from human, animal, and environmental sources. Human Mav-A and Mav-B isolates were the strongest producers; in contrast, animal and environmental Mav-A isolates and human, animal, and environmental Mav-C organisms were low-level producers. Hemolysin production was not restricted to isolates causing invasive infections.