Beta catenin and cytokine pathway dysregulation in patients with manifestations of the "PTEN hamartoma tumor syndrome"

Background. The "PTEN hamartoma tumor syndrome" (PHTS) includes a group of syndromes caused by germline mutations within the tumor suppressor gene "phosphatase and tensin homolog deleted on chromosome ten" (PTEN), characterized by multiple polyps in the gastrointestinal tract and by a highly increased risk of developing malignant tumours in many tissues. The current work clarifies the molecular basis of PHTS in three unrelated Italian patients, and sheds light on molecular pathway disregulation constitutively associated to PTEN alteration. Methods. We performed a combination of RT-PCR, PCR, sequencing of the amplified fragments, Real Time PCR and western blot techniques. Results. Our data provide the first evidence of β-catenin accumulation in blood cells of patients with hereditary cancer syndrome caused by germ-line PTEN alteration. In addition, for the first time we show, in all PHTS patients analysed, alterations in the expression of TNFα, its receptors and IL-10. Importantly, the isoform of TNFRI that lacks the DEATH domain (TNFRSF1β) was found to be overexpressed. Conclusion. In light of our findings, we suggest that the PTEN pathway disregulation could determine, in non-neoplastic cells of PHTS patients, cell survival and pro-inflammatory stimulation, mediated by the expression of molecules such as β-catenin, TNFα and TNFα receptors, which could predispose these patients to the development of multiple cancers

Long term results on the severity of acute appendicitis during COVID-19 pandemic

Background: Acute appendicitis cases increased in severity following COVID-19 related restrictions in March, 2020 [1,2]. We investigated if similar changes occurred during Wave 2. Methods: Acute appendicitis patients during Wave 1 were grouped 8 weeks before (Group A) and after (Group B) stay-at-home restrictions were initiated on March 15, 2020. Cases in Wave 2 were grouped 8 weeks before (Group C) and after (Group D) November 6, 2020. Groups were compared to equivalent time frames in 2018/2019. Results: Group A vs B revealed 42.6% decrease (CI: - 59.4, - 25.7) in uncomplicated appendicitis, and 21.1% increase (CI: 4.8, 37.3) in perforated appendicitis. Similar patterns were noted comparing Group C vs D without statistical significance. The changes seen in Wave 1 were significantly different than in 2018/2019. This trend continued in Wave 2. Conclusions: Similar to Wave 1, acute appendicitis cases increased in severity during wave 2 of COVID-19, but with less prominence. Keywords: Appendicitis; COVID-19; Incidence; Pandemic; Severity

Increasing incidence of complicated appendicitis during COVID-19 pandemic

Background: The novel coronavirus (COVID-19) strain has resulted in restrictions potentially impacting patients presenting with acute appendicitis and their disease burden. Methods: All acute appendicitis admissions (281 patients) between 1/1/2018-4/30/2020 were reviewed. Two groups were created: 6 weeks before (Group A) and 6 weeks after (Group B) the date elective surgeries were postponed in Massachusetts for COVID-19. Acute appendicitis incidence and disease characteristics were compared between the groups. Similar time periods from 2018 to 2019 were also compared. Results: Fifty-four appendicitis patients were categorized in Group A and thirty-seven in Group B. Those who underwent surgery were compared and revealed a 45.5% decrease (CI: 64.2,-26.7) in uncomplicated appendicitis, a 21.1% increase (CI:3.9,38.3) in perforated appendicitis and a 29% increase (CI:11.5,46.5) in gangrenous appendicitis. Significant differences in the incidence of uncomplicated and complicated appendicitis were also noted when comparing 2020 to previous years. Conclusions: The significant increase in complicated appendicitis and simultaneous significant decrease in uncomplicated appendicitis during the COVID-19 pandemic indicate that patients are not seeking appropriate, timely surgical care. Keywords: Acute appendicitis; COVID-19; Complicated appendicitis

Herb–Drug Interactions with St John’s Wort (Hypericum perforatum): an Update on Clinical Observations

St John’s wort (SJW) extracts, prepared from the aerial parts of Hypericum perforatum, contain numerous pharmacologically active ingredients, including naphthodianthrones (e.g., hypericin and its derivatives), phloroglucinols derivatives (e.g., hyperforin, which inhibits the reuptake of a number of neurotransmitters, including serotonin), and flavonoids. Such extracts are widely used for the treatment of mild-to-moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, relevant and, in some case, life-threatening interactions have been reported, particularly with drugs which are substrate of cytochrome P450 and/or P-glycoprotein. Well-documented SJW interactions include (1) reduced blood cyclosporin concentration, as suggested by multiple case reports as well as by clinical trials, (2) serotonin syndrome or lethargy when SJW was given with serotonin reuptake inhibitors, (3) unwanted pregnancies in women while using oral contraceptives and SJW, and (4) reduced plasma drug concentration of antiretroviral (e.g., indinavir, nevirapine) and anticancer (i.e., irinotecan, imatinib) drugs. Hyperforin, which is believed to contribute to the antidepressant action of St John’s wort, is also strongly suspected to be responsible of most of the described interactions

Pancreatic surgery outcomes: multicentre prospective snapshot study in 67 countries

Background: Pancreatic surgery remains associated with high morbidity rates. Although postoperative mortality appears to have improved with specialization, the outcomes reported in the literature reflect the activity of highly specialized centres. The aim of this study was to evaluate the outcomes following pancreatic surgery worldwide.Methods: This was an international, prospective, multicentre, cross-sectional snapshot study of consecutive patients undergoing pancreatic operations worldwide in a 3-month interval in 2021. The primary outcome was postoperative mortality within 90 days of surgery. Multivariable logistic regression was used to explore relationships with Human Development Index (HDI) and other parameters.Results: A total of 4223 patients from 67 countries were analysed. A complication of any severity was detected in 68.7 percent of patients (2901 of 4223). Major complication rates (Clavien-Dindo grade at least IIIa) were 24, 18, and 27 percent, and mortality rates were 10, 5, and 5 per cent in low-to-middle-, high-, and very high-HDI countries respectively. The 90-day postoperative mortality rate was 5.4 per cent (229 of 4223) overall, but was significantly higher in the low-to-middle-HDI group (adjusted OR 2.88, 95 per cent c.i. 1.80 to 4.48). The overall failure-to-rescue rate was 21 percent; however, it was 41 per cent in low-to-middle-compared with 19 per cent in very high-HDI countries.Conclusion: Excess mortality in low-to-middle-HDI countries could be attributable to failure to rescue of patients from severe complications. The authors call for a collaborative response from international and regional associations of pancreatic surgeons to address management related to death from postoperative complications to tackle the global disparities in the outcomes of pancreatic surgery (NCT04652271; ISRCTN95140761)

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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