Dapsone hydroxylamine-mediated alterations in human red blood cells from endometriotic patients

Endometriosis, an estrogen-dependent chronic gynecological disease in women of reproductive age, is characterized by a systemic inflammation status involving also red blood cells (RBCs). In this study, we evaluated how the protein oxidative status could be involved in the worsening of RBC conditions due to dapsone intake in endometriotic women in potential treatment for skin or infection diseases. Blood samples from two groups of volunteers, control group (CG) and endometriosis patient group (PG), were analyzed for their content of band 3 tyrosine phosphorylation (Tyr-P) and high molecular weight aggregate (HMWA) in membranes, and glutathione (GSH) content and carbonic anhydrase (CA) activity in cytosol. In endometriotic patients, RBC showed the highest level of oxidative-related alterations both in membrane and cytosol. More interestingly, the addition of dapsone hydroxylamine (DDS-NHOH) could induce further increase of both membranes and cytosol markers, with an enhancement of CA activity reaching about 66% of the total cell enzyme amount. In conclusion, in PG the systemic inflammatory status leads to the inability of counteracting adjunctive oxidative stress, with a potential involvement of CA-related pathologies, such as glaucoma. Hence, the importance of the evaluation of therapeutic approaches worsening oxidative imbalance present in PG RBC is underlined.     

SARS-CoV-2 Specific Immune Response and Inflammatory Profile in Advanced HIV-Infected Persons during a COVID-19 Outbreak

The main aim of this study was to describe the clinical and immunological outcomes, as well as the inflammatory profile, of patients with advanced HIV in an assisted-living facility in which an outbreak of SARS-CoV-2 occurred. SARS-CoV-2 humoral and specific T-cell response were analyzed in patients with HIV infection and COVID-19; as a secondary objective of the analysis, levels of the inflammatory markers (IL-1β, IL-6, IL-8, and TNFα) were tested in the HIV/COVID-19 group, in HIV-positive patients without COVID-19, and in HIV-negative patients with mild/moderate COVID-19. Antibody kinetics and ability to neutralize SARS-CoV-2 were evaluated by ELISA assay, as well as the inflammatory cytokines; SARS-CoV-2 specific T-cell response was quantified by ELISpot assay. Mann–Whitney or Kruskal–Wallis tests were used for comparisons. Thirty patients were included with the following demographics: age, 57 years old (IQR, 53–62); 76% male; median HIV duration of infection, 18 years (15–29); nadir of CD4, 57/mmc (23–100) current CD4 count, 348/mmc (186–565). Furthermore, 83% had at least one comorbidity. The severity of COVID-19 was mild/moderate, and the overall mortality rate was 10% (3/30). Additionally, 90% of patients showed positive antibody titers and neutralizing activity, with a 100% positive SARS-CoV-2 specific T-cell response over time, suggesting the ability to induce an effective specific immunity. Significantly higher levels of IL-6, IL-8, and TNF-α in COVID-19 without HIV vs. HIV/COVID-19 patients (p < 0.05) were observed. HIV infection did not seem to negatively impact COVID-19-related inflammatory state and immunity. Further data are mandatory to evaluate the persistence of these immunity and its ability to expand after exposure and/or vaccination.     

Reflux and aerodigestive tract diseases

Gastroesophageal reflux disease can present with a wide variety of extraesophageal symptoms. In particular, the type of disease characterized predominately by laryngopharyngeal reflux may be difficult to diagnose because of the absence of regurgitation or heartburn. The available battery of diagnostic tools is often insufficient to confirm a diagnosis of reflux, so the diagnosis is often made by elimination. In many cases, treatment with proton pump inhibitors will relieve symptoms and respiratory complications, despite the persistence of non-acidic reflux. Such treatment is often employed to “confirm” the diagnosis, as measured by patient response. Many diseases have been related to this condition in the literature. The authors review knowledge about these manifestations and their relationship with refluxed gastric content. Physiopathology, symptoms and treatment are reviewed in order to clarify our understanding of laryngopharyngeal reflux diseases and related manifestations.     

Neck dissection: past, present and future?

With the exception of distant metastasis, the presence of cervical lymph node metastasis is the single most adverse independent prognostic factor in head and neck squamous cell carcinoma. Surgical removal of metastatic cervical lymph nodes had been attempted during the late nineteenth century, with varying techniques and poor results. A systematic approach to en bloc removal of cervical lymph node disease, described in detail by Jawdyński at the end of the nineteenth century and popularized and illustrated by Crile in the early twentieth century, provided consistent and more effective treatment and forms the basis of our current techniques. The concepts of radical neck dissection, employed extensively by Martin, were followed with almost religious consistency by most head and neck surgeons until the late twentieth century, when the principles of 'functional' neck dissection, developed by Suárez and popularized by Bocca, Gavilán, Ballantyne, Byers and others, led to the acceptance of modified radical neck dissection as treatment for lymph node disease in various stages. More recently, selective neck dissection, involving removal of nodes confined to the levels at greatest risk of metastasis from primary tumours at various sites, has become accepted practice for elective and, in some instances, therapeutic treatment of the neck. In the future, sentinel lymph node biopsy and the use of molecular pathological analyses may be employed to predict the presence of occult cervical disease, thus directing therapy to patients at greatest risk and sparing those without regional metastasis.     

Paraneoplastic syndromes in patients with laryngeal neuroendocrine carcinomas: clinical manifestations and prognostic significance

Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the larynx. There are a total of ten patients reported with paraneoplastic syndromes associated with laryngeal neuroendocrine carcinomas in the literature. Of these, nine died and the tenth is alive with liver metastases. There were five cases of small-cell neuroendocrine carcinoma, four cases of moderately differentiated neuroendocrine carcinoma, and one case of well-differentiated neuroendocrine carcinoma associated with paraneoplastic syndromes. As these syndromes have significant clinical relevance, physicians should be aware of the possible presence of paraneoplastic syndromes in the diagnostic process of patients with neuroendocrine carcinoma of the larynx.     

A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells

Background

Mutations of the p53 oncosuppressor gene are amongst the most frequent aberration seen in human cancer. Some mutant (mt) p53 proteins are prone to loss of Zn(II) ion that is bound to the wild-type (wt) core, promoting protein aggregation and therefore unfolding. Misfolded p53 protein conformation impairs wtp53-DNA binding and transactivation activities, favouring tumor growth and resistance to antitumor therapies. Screening studies, devoted to identify small molecules that reactivate mtp53, represent therefore an attractive anti-cancer therapeutic strategy. Here we tested a novel fluorescent curcumin-based Zn(II)-complex (Zn-curc) to evaluate its effect on mtp53 reactivation in cancer cells.

Methods

P53 protein conformation was examined after Zn-curc treatment by immunoprecipitation and immunofluorescence assays, using conformation-specific antibodies. The mtp53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The intratumoral Zn-curc localization was evaluated by immunofluorescence analysis of glioblastoma tissues of an ortothopic mice model.

Results

The Zn-curc complex induced conformational change in p53-R175H and -R273H mutant proteins, two of the most common p53 mutations. Zn-curc treatment restored wtp53-DNA binding and transactivation functions and induced apoptotic cell death. In vivo studies showed that the Zn-curc complex reached glioblastoma tissues of an ortothopic mice model, highlighting its ability to crossed the blood-tumor barrier.

Conclusions

Our results demonstrate that Zn-curc complex may reactivate specific mtp53 proteins and that may cross the blood-tumor barrier, becoming a promising compound for the development of drugs to halt tumor growth.     

Feasibility and safety of vaginal myomectomy: a prospective pilot study

STUDY OBJECTIVE: Classic myomectomy was performed via laparotomy. More recently, laparoscopic myomectomy has become a valuable treatment option. Vaginal myomectomy is a surgical procedure that has recently been evaluated. However, few trials have been reported in past literature. The aim of this study was to evaluate feasibility and complication rate of patients submitted to vaginal myomectomy. DESIGN: Prospective study with review of literature (Canadian Task Force classification II-2). SETTING: Department of Obstetrics and Gynecology, S. Filippo Neri Hospital of Rome, Italy. PATIENTS: Consecutive patients with symptomatic myomas who refused hysterectomy. INTERVENTIONS: After preoperative assessment, patients were submitted to vaginal myomectomy using posterior colpotomy. MEASUREMENTS AND MAIN RESULTS: Operative time, perioperative complications, and hospital stay were prospectively recorded. Follow-up examinations were performed at 1 and 12 months postoperatively. Data on possible symptoms, fertility, and pregnancy outcome during follow-up periods were recorded. Myomectomy was completed vaginally in 17 (94%) of 18 patients. Mean operating time was 48 +/- 22 minutes; mean operative blood loss and hospital stay were 210 +/- 350 mL and 3.5 +/- 2.4 days, respectively. Only 2 (11%) patients required blood transfusion. Three patients have conceived spontaneously. CONCLUSION: Vaginal myomectomy is a feasible and safe surgical procedure, with low morbidity and short hospital stay, and could represent a valid alternative to open or laparoscopic myomectomy in selected cases.