Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks.

In this minireview we focus on Hsp60 as a target for anticancer therapy. We discuss the new concepts of chaperonopathies and chaperonotherapy and present information on Hsp60 localization in the cell membrane of human tumor cells. We describe novel mechanisms for Hsp60 reaching the extracellular environment that involve membrane-associated stages, as well as data on anti-Hsp60 antibodies found in human sera, both in normal subjects and patients affected by autoimmune diseases. Finally, we discuss possible therapeutic applications of anti-Hsp60 antibodies in cancer treatment, evaluating also side effects on non-tumor cells. In conclusion, the way for investigating Hsp60-targeted anti-tumor therapy is open, at least for those tumors that express Hsp60 on its surface and/or secrete it outside the cell, as is the search for the molecular mechanisms involved in Hsp60 translocation from cytosol to cell membrane: elucidation of this mechanism will greatly facilitate the optimization of chaperonotherapy centered on Hsp60 with anti-tumor efficacy and minimal side effects

Molecular mimicry in the post-COVID-19 signs and symptoms of neurovegetative disorders?

Many individuals who have severe forms of COVID-19 experience a suite of neurovegetative signs and symptoms (eg, tachycardia) after their recovery, suggesting that the imbalance of the sympathetic-parasympathetic activity of the autonomic nervous system1 could continue for many weeks or months after respiratory symptoms stop. Moreover, a reduction of the parasympathetic tone could have a role in restricting the cholinergic anti-inflammatory pathway, thus favouring hyperinflammation and cytokine storm in the most severe phases of the disease. As reported by Guglielmo Lucchese in The Lancet Microbe,2 SARS-CoV-2 can damage the nervous system via an indirect mechanism, resulting in a high prevalence of autoantibodies, mainly against unknown autoantigens in the brain, in cerebrospinal fluid from patients with neurological complications.2 The cause of low vagal tone and SARS-CoV-2 has not yet been investigated sufficiently and here we would like to share some original data supporting the putative role of molecular mimicry as the culprit of COVID-19 pathogenesis, including the post-COVID-19 neurovegetative syndrome.2, 3, 4, 5 Using methods that have been previously described,3 we looked specifically at the human proteins expressed in vagal nuclei and ganglia. As shown in the appendix (pp 1–2), we found that 22 of these proteins share peptides that could putatively generate a T-cell or B-cell driven autoimmune response. The location and function of these proteins are described in the appendix (pp 3–24). Fibres of the vagal nerve originate from four nuclei located in the medulla oblongata—ie, the dorsal motor nucleus, the nucleus ambiguus, the solitary nucleus, and, to a lesser extent, the spinal trigeminal nucleus. These fibres contribute to the somatic and visceral motricity, somatic and visceral sensibility, and the sense of taste. The visceral motor inputs originate specifically from the dorsal motor nucleus and nucleus ambiguus and are directed towards the heart, the airways, and the gastrointestinal system. Moreover, the vagal visceral innervation includes two sensory ganglia of the peripheral nervous system—the nodose ganglion and the jugular ganglion. In particular, peripheral fibres of the neurons of the nodose ganglion not only innervate the taste buds on the epiglottis, the chemoreceptors of the aortic bodies, and baroreceptors in the aortic arch, but they also provide sensory innervation to the circulatory, respiratory, and gastrointestinal systems. An impairment of the vagal innervation of the heart can lead to tachycardia at rest, which is often seen by clinicians during physical examination of patients who have recovered from a severe form of COVID-19.1 We found that the dorsal motor nucleus, nucleus ambiguus, nodose ganglion, and jugular ganglion can all host neurons presenting proteins with epitopes in common with SARS-CoV-2 proteins, and the peptide TGRLQSL is embedded in one immunoreactive linear epitope that has already been experimentally validated in the human host (Immune Epitope Database and Analysis Resource identification number 36724) to be able to generate an autoimmune response. We share our findings to prompt further studies assessing whether severe forms of COVID-19 could produce transitory or permanent damage in some vagal structure and whether this can, in turn, be responsible for the low vagal tone and the related clinical signs and symptoms

Gd-EOB-DTP-enhanced MRC in the preoperative percutaneous management of intra and extrahepatic biliary leakages: Does it matter?

Postoperative bile leakage is a common complication of abdominal surgical procedures and a precise localization of is important to choose the best management. Many techniques are available to correctly identify bile leaks, including ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI), being the latter the best to clearly depict "active" bile leakages. This paper presents the state of the art algorithm in the detection of biliary leakages in order to plan a percutaneous biliary drainage focusing on widely available and safe contrast agent, the Gb-EOB-DPA. We consider its pharmacokinetic properties and impact in biliary imaging explain current debates to optimize image quality. We report common sites of leakage after surgery with special considerations in cirrhotic liver to show what interventional radiologists should look to easily detect bile leaks

Trans-epithelial transport of the betalain pigments indicaxanthin and betanin across Caco-2 cell monolayers and influence of food matrix

Purpose: This study investigated the absorption mechanism of the phytochemicals indicaxanthin and betanin and the influence of their food matrix (cactus pear and red beet) on the intestinal transport. Methods: Trans-epithelial transport of dietary-consistent amounts of indicaxanthin and betanin in Caco-2 cell monolayers seeded on TranswellR inserts was measured in apical to basolateral (AP-BL) and basolateral to apical (BL-AP) direction, under an inwardly directed pH gradient (pH 6.0/7.4, AP/BL) mimicking luminal and serosal sides of human intestinal epithelium. The effect of inhibitors of membrane transporters on the absorption was also evaluated. Contribution of the paracellular route was investigated after EDTA treatment of the cell monolayer. In vitro digestion of betalainic food was performed to provide a post-intestinal fraction containing bioaccessible pigments. Results: Apparent permeability coefficients (P app) in the absorptive direction were (4.4 ± 0.4) × 10-6 and (3.2 ± 0.3) × 10-6 cm s-1 for indicaxanthin and betanin, respectively. Transport of indicaxanthin was non-polarized, linear as a function of time and concentration, and unaffected by inhibitors of membrane transporters. Betanin exhibited significantly different bidirectional P app values and non-linear efflux kinetics. The concentration- dependent betanin efflux was described by a kinetic model including one non-saturable (K d = 0.042 μL cm-2 min-1) and one saturable component identified as the apical multidrug resistance-associated protein 2 (MRP2; K m = 275 μM; J max = 42 pmol min-1 cm-2). Permeation of both betalains increased remarkably after EDTA treatment of the cell monolayer. Neither indicaxanthin nor betanin underwent metabolic transformation. Food matrix did not affect trans-epithelial transfer of indicaxanthin, but reduced the absorption rate of betanin, red beet more than cactus pear. Conclusions: Dietary indicaxanthin and betanin can substantially be absorbed through paracellular junctions of intestinal epithelial cells. Additional trans-membrane permeation can be considered for betanin, whose absorption is limited by a MRP2-mediated efflux and negatively affected by its food matrix. Present findings are consistent with the quite higher bioavailability of indicaxanthin over betanin established in humans. © 2012 Springer-Verlag

The predictive role of pelvic magnetic resonance in the follow up of spontaneous or induced puberty in turner syndrome

Puberty is a critical age for patients with Turner syndrome (TS): infertility is reported to be linked to karyotype and spontaneous puberty and menarche occur in approximately 30% of patients, especially in mosaicism. However, it is not always predictable considering hormonal pattern and pelvic transabdominal ultrasound scan (US). The aim of the study is to compare the accuracy of Magnetic Resonance Imaging (MRI) and US to evaluate uterine and gonads volume, to visualize the presence of follicles and to predict spontaneous puberty and menarche in girls with TS. In a retrospective study, we evaluated 19 TS patients (age: 9-16 years), who underwent transabdominal pelvic US and pelvic MRI as required by parents. We correlated pelvic imaging with karyotype, hormonal data and pubertal outcome, and we compared US resolution to MRI. MRI revealed a higher accuracy in the study of uterus and ovaries, and permitted to measure ovaries not visualized by US. Ovarian volume, the presence of follicles and the occurrence of spontaneous puberty were not related to the karyotype; spontaneous puberty started in one patient with a karyotype 45,X and in two patients with mosaicism (45,X/46,XX; 47,XXX/45, X). Ovarian follicles were relieved by MRI in patients with a spontaneous menarche and the persistence of menstrual cycles correlated with an ovarian volume corresponding to Tanner stage 3-4. We stress the role of MRI in the follow-up of TS adolescents, guide in the choice of the timing of treatment

Mobility of daughter elements of U-238 decay chain during leaching by In Situ Recovery (ISR) : New insights from digital autoradiography

In highly permeable sedimentary rock formations, U extraction by in-situ leaching techniques (ISR - In-Situ Recovery) is generally considered to have a limited environmental impact at ground level. Significantly, this method of extraction produces neither mill tailings nor waste rocks. Underground, however, the outcome for U-238 daughter elements in aquifers is not well known because of their trace concentrations in the host rocks. Thus, understanding the in-situ mobility of these elements remains a challenge. Two samples collected before and after six months of ISR experiments (Dulaan Uul, Mongolia) were studied with the help of a digital autoradiography technique (DA) of alpha particles, bulk alpha spectrometry, and complementary petrographic observation methods. These techniques demonstrate that before and after leaching, the radioactivity is concentrated in altered and microporous Fe-Ti oxides. Most of the daughter elements of U remain trapped in the rock after the leaching process. DA confirms that the alpha activity of the Fe-Ti oxides remains high after uranium leaching, and the initial secular equilibrium of the U-238 series for Th-230 to Po-210 daughter elements (including Ra-226) of the fresh rocks is maintained after leaching. While these findings should be confirmed by more systematic studies, they already identify potential mechanisms explaining why the U-daughter concentrations in leaching water are low.Peer reviewe

A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model

Chaperonins mediate protein folding in a cavity formed by multisubunit rings. The human CCT has eight non-identical subunits and the His147Arg mutation in one subunit, CCT5, causes neuropathy. Knowledge is scarce on the impact of this and other mutations upon the chaperone’s structure and functions. To make progress, experimental models must be developed. We used an archaeal mutant homolog and demonstrated that the His147Arg mutant has impaired oligomeric assembly, ATPase activity, and defective protein homeostasis functions. These results establish for the first time that a human chaperonin gene defect can be reproduced and studied at the molecular level with an archaeal homolog. The major advantage of the system, consisting of rings with eight identical subunits, is that it amplifies the effects of a mutation as compared with the human counterpart, in which just one subunit per ring is defective. Therefore, the slight deficit of a non-lethal mutation can be detected and characterized

Post-neurosurgical multidrug-resistant Acinetobacter baumannii meningitis successfully treated with intrathecal colistin. A new case and a systematic review of the literature

Introduction: Post-neurosurgical nosocomial meningitis has become an important subgroup of bacterial meningitis in the hospital setting. The increase in meningitis caused by multidrug-resistant (MDR) Acinetobacter baumannii has resulted in a significant reduction in available treatment options. Case report and literature review: We report the case of a 36-year-old man with a complex craniofacial trauma, who developed a nosocomial meningitis due to MDR A. baumannii that was cured by intrathecal colistin. The case is contextualized among all the published cases of Acinetobacter meningitis treated with topical colistin found through a MEDLINE search of the literature. To date, including the present case, eight reported cases of Acinetobacter meningitis have been treated with colistin administered by an intrathecal route and 24 by an intraventricular route. The daily dose of colistin used ranged from 1.6 mg every 24 h to 20 mg every 24 h in adult patients. Themedian time necessary to obtain cerebrospinal fluid sterilization was 4.1 days, and treatment was always successful even if in two cases Acinetobacter meningitis relapsed. Toxicity probably or possibly related to the topical administration of colistin was noted in five out of the 32 patients. Conclusions: Topical colistin can be an effective and safe treatment for MDR Acinetobacter meningitis

Percutaneous Application of High Power Microwave Ablation With 150 W for the Treatment of Tumors in Lung, Liver, and Kidney: A Preliminary Experience

Objective: The aim of this study is to evaluate the feasibility, safety, and short-term effectiveness of a high-power (150 W) microwave ablation (MWA) device for tumor ablation in the lung, liver, and kidney. Methods: Between December 2021 and June 2022, patients underwent high-power MWA for liver, lung, and kidney tumors. A retrospective observational study was conducted in accordance with the Declaration of Helsinki. The MWA system utilized a 150-W, 2.45-GHz microwave generator (Emprint™ HP Ablation System, Medtronic). The study assessed technical success, safety, and effectiveness, considering pre- and post-treatment diameter and volume, lesion location, biopsy and/or cone beam computed tomography (CBCT) usage, MWA ablation time, MWA power, and dose-area product (DAP). Results: From December 2021 to June 2022, 16 patients were enrolled for high-power MWA. Treated lesions included hepatocellular carcinoma (10), liver metastasis from colon cancer (1), liver metastasis from pancreatic cancer (1), squamous cell lung carcinoma (2), renal cell carcinoma (1), and renal oncocytoma (1). Technical success rate was 100%. One grade 1 complication (6.25%) was reported according to CIRSE classification. Overall effectiveness was 92.8%. Pre- and post-treatment mean diameters for liver lesions were 19.9 mm and 37.5 mm, respectively; for kidney lesions, 34 mm and 35 mm; for lung lesions, 29.5 mm and 31.5 mm. Pre- and post-treatment mean volumes for liver lesions were 3.4 ml and 24 ml, respectively; for kidney lesions, 8.2 ml and 20.5 ml; for lung lesions, 10.2 ml and 32.7 ml. The mean ablation time was 48 minutes for liver, 42.5 minutes for lung, and 42.5 minutes for renal ablation. The mean DAP for all procedures was 40.83 Gcm2. Conclusion: This preliminary study demonstrates the feasibility, safety, and effectiveness of the new 150 W MWA device. Additionally, it shows reduced ablation times for large lesions

Expression of telomeric repeat binding factor-1 in astroglial brain tumors

OBJECTIVE: In human somatic cells, telomeres shorten with successive cell divisions, resulting in progressive genomic instability, altered gene expression, and cell death. Recently, telomere-specific deoxyribonucleic acid-binding proteins, such as telomeric repeat binding factor-1 (TRF1), have been proposed as candidates for the role of molecules regulating telomerase activity, and they have been suggested to play key roles in the maintenance of telomere function. The present study was designed to assess TRF1 expression in human astroglial brain tumors and to speculate on the clinical implications of its expression. METHODS: Twenty flash-frozen surgical specimens obtained from adult patients who underwent craniotomy for microsurgical tumor resection, histologically verified as World Health Organization Grade II to IV astrocytomas, were used. Expression of TRF1 in astrocytomas of different grades was studied by means of both immunohistochemical and Western blotting analysis. The correlation between the extent of TRF1 expression and histological grading, performance status, and length of survival of patients underwent statistical analyses. RESULTS: TRF1 was expressed in all tumor samples. The level of its expression was variable, decreasing from low-grade through high-grade astrocytomas (P 0.0032). TRF1 expression correlated with the patient’s length of survival (P 0.001) and performance status (P 0.001) and proved to be an independent indicator of length of survival. CONCLUSION: Our findings suggest that the loss of TRF1 expression capability, as a result of down-regulation of TRF1 expression in malignant gliomas cells, may play a role in the malignant progression of astroglial brain tumors