Molecular Mechanisms of AKI in the Elderly: From Animal Models to Therapeutic Intervention

Acute kidney injury (AKI), a critical syndrome characterized by a sudden reduction of renal function, is a common disorder among elderly patients particularly in Intensive Care Unit (ICU). AKI is closely associated with both short- and long-term mortality and length of hospital stay and is considered a predictor of chronic kidney disease (CKD). Specific hemodynamic, metabolic, and molecular changes lead to increased susceptibility to injury in the aged kidney; therefore, certain causes of AKI such as the prerenal reduction in renal perfusion or vascular obstructive conditions are more common in the elderly; moreover, AKI is often multifactorial and iatrogenic. Older patients present several comorbidities (diabetes, hypertension, heart failure) and are exposed to multiple medical interventions such as the use of nephrotoxic contrasts media and medications, which can also trigger AKI. Considering the emerging relevance of this condition, prevention and treatment of AKI in the elderly should be crucial in the internist and emergency setting. This review article summarizes the incidence, the risk factors, the pathophysiology, the molecular mechanisms and the strategies of prevention and treatment of AKI in elderly patients

RAS/BRAF mutational status in familial non‑medullary thyroid carcinomas: A retrospective study

There are contrasting views on whether familial non‑medullary thyroid carcinomas (FNMTCs) are characterized by aggressive behavior, and limited evidence exists on the prognostic value of BRAF and RAS mutations in these tumors. Thus, in the present study, clinicopathological features were analyzed in 386 non‑medullary thyroid carcinomas (NMTCs), subdivided in 82 familial and 304 sporadic cases. Furthermore, the RAS and BRAF mutational statuses were investigated in a subgroup of 34 FNMTCs to address their clinical and biological significance. The results demonstrated that, compared with sporadic NMTCs, FNMTCs are characterized by significantly higher rates of multicentricity and bilaterality and are more frequently associated with chronic autoimmune thyroiditis. Notably, a statistically significant difference in the rates of multicentricity was observed by subgrouping familial tumors according to the number of relatives involved; those with ≥3 affected relatives were more likely to be multicentric. Furthermore, the FNMTC cohort exhibited higher rates of tumors >4 cm in size with extrathyroidal or lymph node involvement. However, no significant difference was observed. Similarly, no differences were observed with respect to the age of onset or the patient outcome. The mutational profiling exhibited a rate of 58.8% for BRAF V600E mutations in familial tumors, which is at the upper limit of the mutational frequency observed in historical series of sporadic thyroid cancer. A high rate of NRAS mutations (17.6%) was also observed, mostly in the follicular variant histotype. Notably, compared with BRAF/RAS‑wild type FNMTCs, the familial carcinomas bearing BRAF or NRAS mutations exhibited slightly higher rates of bilaterality and multicentricity, in addition to increased frequency of locally advanced stage or lymph node involvement. The present data support the theory that FNMTCs are characterized by clinicopathological features that resemble a more aggressive phenotype and suggest that RAS/BRAF mutational analysis deserves to be further evaluated as a tool for the identification of FNMTCs with a potentially unfavorable prognosis

Beyond Platinum, ICIs in Metastatic Cervical Cancer: A Systematic Review

Background: Cervical cancer (CC) constitutes the fourth most common tumor among the female population. Therapeutic approaches to advanced CC are limited, with dismal results in terms of survival, mainly after progression to platinum-based regimens. Immune checkpoint inhibitors (ICIs) are remodeling the therapeutic scenario of many solid tumors. The role of ICIs in CC should be addressed. Therefore, we systematically reviewed the latest clinical trials employing ICIs in advanced CC to assess which ICIs have been employed and how ICIs might meet the need for new therapeutic options in terms of efficacy and safety. Methods: The review was conducted following the PRISMA guidelines. The following efficacy outcomes were specifically collected: overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS); for safety: type, number, and grade of adverse events (AEs). Results: A total of 17 studies were analyzed. Anti-PD1 (pembrolizumab, nivolumab, cemiplimab, balstilimab, and tislelizumab), anti-PD-L1 (atezolizumab), and anti-CTLA-4 (ipilimumab, zalifrelimab) agents were employed both as single agents or combinations. Overall ORR ranged from 0% to 65.9%. ORR ranged from 5.9% to 69.6% in PD-L1-positive patients and from 0% to 50% in PD-L1-negative patients. DCR was 30.6–94.1%. mPFS ranged from 2 to 10.4 months. mOS ranged from 8 months to not reached. PD-L1 status did not impact survival. A total of 33.9% to 100% of patients experienced AEs. Conclusion: Immunotherapy represents an appealing strategy for patients with advanced CC, as 2 out of 3 patients seem to respond to ICIs. PD-L1 status might be an indicator of response without impacting survival

Population Genetic History of <i>Aristeus antennatus</i> (Crustacea: Decapoda) in the Western and Central Mediterranean Sea

<div><p><i>Aristeus antennatus</i> is an ecologically and economically important deep-water species in the Mediterranean Sea. In this study we investigated the genetic variability of <i>A</i>. <i>antennatus</i> sampled from 10 sampling stations in the Western and Central Mediterranean. By comparing our new samples with available data from the Western area, we aim to identify potential genetic stocks of <i>A</i>. <i>antennatus</i> and to reconstruct its historical demography in the Mediterranean. We analyzed two regions of mitochondrial DNA in 319 individuals, namely COI and 16S. We found two main results: i) the genetic diversity values consistent with previous data within the Mediterranean and the absence of barriers to gene flow within the Mediterranean Sea; ii) a constant long-term effective population size in almost all demes but a strong signature of population expansion in the pooled sample about 50,000 years B.P./ago. We propose two explanation for our results. The first is based on the ecology of <i>A</i>. <i>antennatus</i>. We suggest the existence of a complex meta-population structured into two layers: a deeper-dwelling stock, not affected by fishing, which preserves the pattern of historical demography; and genetically homogeneous demes inhabiting the fishing grounds. The larval dispersal, adult migration and continuous movements of individuals from “virgin” deeper grounds not affected by fishing to upper fishing areas support an effective ‘rescue effect’ contributing to the recovery of the exploited stocks and explain their genetic homogeneity throughout the Mediterranean Sea. The second is based on the reproduction model of this shrimp: the high variance in offspring production calls for a careful interpretation of the data observed under classical population genetics and Kingman’s coalescent. In both cases, management policies for <i>A</i>. <i>antennatus</i> will therefore require careful evaluation of the meta-population dynamics of all stocks in the Mediterranean. In the future, it will be particularly relevant to sample the deepest ones directly.</p></div

Endocavitary sonography of early oral cavity malignant tumors

Background: Preoperative staging is crucial for oral cancer management. The purpose of this study was to assess the tumor thickness using ultrasound and to correlate the level of histological infiltration with the tumor superficial extension and lesion thickness. Methods: Thirty-two subjects affected by oral cavity carcinoma were prospectively evaluated with intraoral ultrasound. The ultrasound sensitivity, the correlation between the ultrasound level of infiltration, and lesion diameters and thickness were assessed. Results: A 91% ultrasound sensitivity was found with no significant correlation between tumor diameter and level of histological infiltration (P &gt;.05). A thickness of &lt;2 mm was associated to tumor extension to the lamina propria, a value of &gt;6 mm to muscular layer infiltration. Lymph adenopathies were identified in 21% of cases, associated to muscular layer infiltration in all cases. Conclusion: In the study of early oral cavity tumors, ultrasound is accurate for demonstrating the level of tumor infiltration and contributes to the therapeutic choice

Extended Bayesian Skyline Plot (EBSP) of a concatenated 16S rDNA and COI sequences, Western and Central Mediterranean pooled samples.

<p><i>X</i> axis: calendar years. <i>Y</i> axis: effective population size. Red lines show the 95% HPD limits; black line the median estimate.</p