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.     

Pinealectomy interferes with the circadian clock genes expression in white adipose tissue

Melatonin, the main hormone produced by the pineal gland, is secreted in a circadian manner (24‐hr period), and its oscillation influences several circadian biological rhythms, such as the regulation of clock genes expression (chronobiotic effect) and the modulation of several endocrine functions in peripheral tissues. Assuming that the circadian synchronization of clock genes can play a role in the regulation of energy metabolism and it is influenced by melatonin, our study was designed to assess possible alterations as a consequence of melatonin absence on the circadian expression of clock genes in the epididymal adipose tissue of male Wistar rats and the possible metabolic repercussions to this tissue. Our data show that pinealectomy indeed has impacts on molecular events: it abolishes the daily pattern of the expression of Clock, Per2, and Cry1 clock genes and Pparγ expression, significantly increases the amplitude of daily expression of Rev‐erbα, and affects the pattern of and impairs adipokine production, leading to a decrease in leptin levels. However, regarding some metabolic aspects of adipocyte functions, such as its ability to synthesize triacylglycerols from glucose along 24 hr, was not compromised by pinealectomy, although the daily profile of the lipogenic enzymes expression (ATP‐citrate lyase, malic enzyme, fatty acid synthase, and glucose‐6‐phosphate dehydrogenase) was abolished in pinealectomized animals.     

Echogenic Appearance of Colorectal Liver Metastases on Intraoperative Ultrasonography is Associated with Survival After Hepatic Resection

Survival after resection of colorectal liver metastases has traditionally been associated with clinicopathologic factors. We sought to investigate whether echogenicity of colorectal liver metastasis as assessed by intraoperative ultrasound (IOUS) was a prognostic factor after hepatic resection. Prospective data on tumor IOUS appearance were collected in 84 patients who underwent hepatic resection for colorectal liver metastasis. Images were digitally recorded, blindly reviewed, and scored for echogenicity (hypo-, iso-, or hyperechoic). The median tumor number was 1 and the median tumor size was 5.0 cm. At the time of surgery, the IOUS appearance of the colorectal liver metastases were hypoechoic in 35 (41.7%) patients, isoechoic in 37 (44.0%) patients, and hyperechoic in 12 (14.3%) patients. Traditional clinicopathologic prognostic factors were similarly distributed among the three echogenicity groups (all p > 0.05). Patients with a hypoechoic lesion had a significantly shorter median survival (30.2 months) compared with patients who had either an isoechoic (53.2 months) or hyperechoic (42.3 months) lesion (p = 0.005). The 5-year survival after hepatic resection of colorectal liver metastasis was also associated with the echogenic appearance of the lesion (hypoechoic 14.4 vs isoechoic 37.4 vs hyperechoic 46.2%) (p < 0.05). Intraoperative ultrasound echogenicity should be considered a prognostic factor after hepatic resection of metastatic colorectal cancer. This study was presented at the 47th annual meeting of The Society for Surgery of the Alimentary Tract, Los Angeles, CA, USA, 22 May 2006.     

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.