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.     

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.     

Evaluation of Class I ART restorations in Brazilian schoolchildren: three-year results

Atraumetic Restorative Treatment (ART) has been adopted around the world to avoid unnecessary extractions, especially in non-industrialized countries The development of specific glass ionomer cements marketed for the ART technique has contributed to the technical success rate. In this study. Ketac-Molar^a (3M ESPE. Dental Medzn Germany) was used to restore 150 Class I cavities in 118 Brazilian public school children, aged from 7–12 years. At baseline and at subsequent recalls. CPI probes with a ball-end of 0.5 millimeters (mm) were used to assess loss of restorative material, and photographic color transparencies of restorations were made. After six months. 83 patients returned for follow-up examinations, with 71.8% of their restorations designated as acceptable. After three years. 49 patients with 57 ART-restorations were evaluated, with 21.0% of these restorations graded as acceptable Another 29.8% of their restorations had been replaced by more permanent materials. The main objective of the ART technique is tooth retention; this was achieved for 94.7% of the restored teeth in a high caries risk population who returned for recalls.     

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.     

Laparoscopic Deployment of Biliary Self-Expandable Metal Stent (SEMS) for One-Step Palliation in 23 Patients with Advanced Pancreatico-Biliary Tumors—a Pilot Trial

Background Exploratory laparoscopy is commonly undertaken in patients with highly suspicious biliary and pancreatic lesions to facilitate diagnosis and staging cancer is present. If an unresectable tumor is identified, a second endoscopic procedure may be required do deploy a self-expandable metal stent (SEMS) for palliation. As endoscopic retrograde cholangio pancreatography (ERCP) may be unsuccessful in up to 20% of patients, we evaluated the feasibility and safety of deployment of self-expandable metal stents at the same time as the initial laparoscopy. Patients and Methods A total of 23 eligible patients (8 male and 15 female) with malignant obstruction of the common bile duct underwent deployment of SEMS at laparoscopy. Primary outcome measure was the successful laparoscopic deployment of stent and secondary outcome measure was complications rates. Results Indications for stent deployment were unresectable pancreatic cancer in 18, cholangiocarcinoma in two, neuroendocrine tumor in one and ampullary adenocarcinoma in two patients. The median age was 73 years (range 49–93). Twenty-two of 23 stents were deployed successfully: 17 stents were deployed transcystically and five via a choledochotomy. Median times for laparoscopic exploration and SEMS deployment were 165 min (range 105–230) and 20 min (range 10–50), respectively. Pre- and post-procedures median total bilirubin were 9.4 mg/dl (range 5.4–17.5) and 4.0 (range 2.6–7.1). The median size of the pancreatic mass was 3 cm (range 2–5 cm) and that of the common bile duct (CBD) from 9.2 mm (range 7.2–17.4). The mean duration of laparoscopy was 170 min (range 120–230 min) and that for stent deployment 23 min (range 10–50 min). Complications included bleeding, obstruction, and wound infection. Bleeding occurred on day 7 in two patients and on day 30 in one patient; bleeding occurred at the gastrojejunal anastomosis site and was successfully treated with endoscopic hemostasis. A total of three stent obstructions were identified: one each at 60, 90, and 120 days follow-up. All complications were successfully managed endoscopically. There were a total of seven deaths, six as a result of progressive cancer and one of surgical wound infection and ensuing complications. Conclusion This study demonstrates that laparoscopic deployment of self-expandable metal bile duct stents is feasible and safe. This option appears to be a reasonable option in patients with inoperable malignant obstruction of the distal common bile duct.     

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.