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.     

Iatrogenic ureteral lesions and repair: a review for gynecologists

Ureter injuries are a well-known complication of gynecologic surgery and a frequent cause of medicolegal problems. Because there are no randomized, controlled trials and the available studies are small series and case reports, the evidence on which to base treatment is weak. We therefore reviewed the complete English-language literature of ureter repair since 1990. In total, 608 ureter injuries were reported. Although it is widely believed that for laceration or section the prognosis is affected by a delay in diagnosis, we could not find evidence to substantiate this. An obstruction requires stenting only. For a laceration, stenting with suturing was more effective than stenting only (p = .006). A ureter anastomosis was successful in over 94% of cases either by laparotomy or laparoscopy. In conclusion, the literature data are scanty and heterogeneous and do not permit solid conclusions. Evidence, however, is emerging that a laceration should be treated by stenting and suturing. A ureter anastomosis over a stent could become a valid option especially when performed by laparoscopy.     

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.     

The Enterprise,a massive transposon carrying Spok meiotic drive genes

The genomes of eukaryotes are full of parasitic sequences known as transposable elements (TEs). Here, we report the discovery of a putative giant tyrosine-recombinase-mobilized DNA transposon, Enterprise, from the model fungus Podospora anserina. Previously, we described a large genomic feature called the Spok block which is notable due to the presence of meiotic drive genes of the Spok gene family. The Spok block ranges from 110 kb to 247 kb and can be present in at least four different genomic locations within P. anserina, despite what is an otherwise highly conserved genome structure. We propose that the reason for its varying positions is that the Spok block is not only capable of meiotic drive but is also capable of transposition. More precisely, the Spok block represents a unique case where the Enterprise has captured the Spoks, thereby parasitizing a resident genomic parasite to become a genomic hyperparasite. Furthermore, we demonstrate that Enterprise (without the Spoks) is found in other fungal lineages, where it can be as large as 70 kb. Lastly, we provide experimental evidence that the Spok block is deleterious, with detrimental effects on spore production in strains which carry it. This union of meiotic drivers and a transposon has created a selfish element of impressive size in Podospora, challenging our perception of how TEs influence genome evolution and broadening the horizons in terms of what the upper limit of transposition may be.

Transposable elements (TEs) are major agents of change in eukaryotic genomes. Their ability to selfishly parasitize their host replication machinery has large impacts on both genome size and on gene regulation (Chénais et al. 2012). In extreme cases, TEs can contribute up to 85% of genomic content (Schnable et al. 2009), and expansion and reduction of TEs can result in rapid changes in both genome size and architecture (Haas et al. 2009; Möller and Stukenbrock 2017; Talla et al. 2017). Generally, TEs have small sizes (∼50–12,000 bp) and accomplish these large-scale changes through their sheer number. For example, there are ∼1.1 million Alu elements in the human genome, which have had a large impact on genome evolution (Jurka 2004; Bennett et al. 2008). The largest known cases among Class I retrotransposons are long terminal repeat (LTR) elements that can be as large as 30 kb, but among Class II DNA transposons, Mavericks/Polintons are known to grow as large as 40 kb through the capture of additional open reading frames (ORFs) (Arkhipova and Yushenova 2019). Recently, a behemoth TE named Teratorn was described in teleost fish; it can be up to 182 kb in length, dwarfing all other known TEs. Teratorn has achieved this impressive size by fusing a piggyBac DNA transposon with a herpesvirus, thereby blurring the line between TEs and viruses (Inoue et al. 2017, 2018). Truly massive transposons may be lurking in the depths of many eukaryotic genomes, but the limitations of short-read genome sequencing technologies and the lack of population-level high-quality assemblies may make them difficult to identify.The Spok block is a large genomic feature that was first identified thanks to the presence of the spore killing (Spok) genes in species from the genus Podospora (Grognet et al. 2014; Vogan et al. 2019). The Spoks are selfish genetic elements that bias their transmission to the next generation in a process known as meiotic drive. Here, drive occurs by inducing the death of spores that do not inherit them, through a single protein that operates as both a toxin and an antidote (Grognet et al. 2014; Vogan et al. 2019). The first Spok gene described, Spok1, was discovered in Podospora comata (Grognet et al. 2014). In P. anserina, the homologous gene Spok2 is found at high population frequencies, whereas two other genes of the Spok family, Spok3 and Spok4, are at low to intermediate frequencies (Vogan et al. 2019). Unlike Spok1 and Spok2, however, Spok3 and Spok4 are always associated with a large genomic region (the Spok block). The Spok block can be located at different chromosomal locations in different individuals but is never found more than once in natural strains. The number of Spok genes and the location of the Spok block (which carries Spok3, Spok4, or both) define the overall meiotic driver behavior of a given genome, which can be classified into the so-called Podospora spore killers or Psks (van der Gaag et al. 2000; Vogan et al. 2019). The Spok block stands out not only because of its size, typically around 150 kb, but also because there is otherwise high genome collinearity among strains of P. anserina and with the related species P. comata and P. pauciseta (Vogan et al. 2019).The fact that the Spok block is found at unique genomic positions between otherwise highly similar strains is of prime interest as each novel Spok block position creates a unique meiotic drive type (Psk) due to the intricacies of meiosis in Podospora (Vogan et al. 2019). We therefore set out to determine the mechanism through which the Spok block relocates throughout the genome. Additionally, we annotated the gene content of the various Spok blocks to describe their composition and understand what represents the minimal component of the Spok block. Lastly, we conducted fitness assays to investigate whether the presence of the Spok block imparts any detrimental effects upon the host.