Human SLFN5 and its Xenopus Laevis ortholog regulate entry into mitosis and oocyte meiotic resumption.

The Schlafen gene family was first described in mice as a regulator of thymocyte development. Further studies showed involvement of human orthologs in different processes related with viral replication, cellular proliferation, and differentiation. In recent years, a new role for human Slfn11 in DNA replication and chromatin remodeling was described. As commonly observed in many gene families, Slfn paralogs show a tissue-specific expression. This made it difficult to reach conclusions which can be valid in different biological models regarding the function of the different Schlafen proteins. In the present study, we investigate the involvement of SLFN5 in cell-cycle regulation and cell proliferation. A careful analysis of SLFN5 expression revealed that SLFN5 is highly expressed in proliferating tissues and that the protein is ubiquitously present in all the tissues and cell line models we analyzed. Very interestingly, SLFN5 expression oscillates during cell cycle, peaking during S phase. The fact that SLFN5 interacts with protein phosphatase 2A and that SLFN5 depletion causes cell cycle arrest and cellular apoptosis, suggests a direct involvement of this human paralog in cell cycle progression and cellular proliferation. We substantiated our in vitro and in cellulo results using Xenopus laevis oocytes to show that mRNA depletion of the unique Slfn gene present in Xenopus, whose protein sequence shares 80% of homology with SLFN5, recapitulates the phenotype observed in human cells preventing the resumption of meiosis during oocyte development.

Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061.

Protein phosphatase 2A (PP2A) is an abundant phosphoprotein phosphatase that acts as a tumor suppressor. For this reason, compounds able to activate PP2A are attractive anticancer agents. The compounds iHAP1 and DT-061 have recently been reported to selectively stabilize specific PP2A-B56 complexes to mediate cell killing. We were unable to detect direct effects of iHAP1 and DT-061 on PP2A-B56 activity in biochemical assays and composition of holoenzymes. Therefore, we undertook genome-wide CRISPR-Cas9 synthetic lethality screens to uncover biological pathways affected by these compounds. We found that knockout of mitotic regulators is synthetic lethal with iHAP1 while knockout of endoplasmic reticulum (ER) and Golgi components is synthetic lethal with DT-061. Indeed we showed that iHAP1 directly blocks microtubule assembly both in vitro and in vivo and thus acts as a microtubule poison. In contrast, DT-061 disrupts both the Golgi apparatus and the ER and lipid synthesis associated with these structures. Our work provides insight into the biological pathways perturbed by iHAP1 and DT-061 causing cellular toxicity and argues that these compounds cannot be used for dissecting PP2A-B56 biology.

Surgical versus medical treatment of type 2 diabetes mellitus in nonseverely obese patients: a systematic review and meta-analysis.

OBJECTIVE: To compare surgical versus medical treatment of type 2 diabetes mellitus (T2DM) remission and comorbidities in patients with a body mass index (BMI) less than 35 kg/m2. BACKGROUND: Obesity surgery can achieve remission of T2DM and its comorbidities. Metabolic surgery has been proposed as a treatment option for diabetic patients with BMI less than 35 kg/m2 but the efficacy of metabolic surgery has not been conclusively determined. METHODS: A systematic literature search identified randomized (RCT) and nonrandomized comparative observational clinical studies (OCS) evaluating surgical versus medical T2DM treatment in patients with BMI less than 35 kg/m2. The primary outcome was T2DM remission. Additional analyses comprised glycemic control, BMI, HbA1c level, remission of comorbidities, and safety. Random effects meta-analyses were calculated and presented as weighted odds ratio (OR) or mean difference (MD) with 95% confidence intervals (95% CI). RESULTS: Five RCTs and 6 OCSs (706 total T2DM patients) were included. Follow-up ranged from 12 to 36 months. Metabolic surgery was associated with a higher T2DM remission rate (OR: 14.1, 95% CI: 6.7-29.9, P < 0.001), higher rate of glycemic control (OR: 8.0, 95% CI: 4.2-15.2, P < 0.001) and lower HbA1c level (MD: -1.4%, 95% CI -1.9% to -0.9%, P < 0.001) than medical treatment. BMI (MD: -5.5 kg/m2, 95% CI: -6.7 to -4.3 kg/m2, P < 0.001), rate of arterial hypertension (OR: 0.25, 95% CI: 0.12-0.50, P < 0.001) and dyslipidemia (OR: 0.21, 95% CI: 0.10-0.44, P < 0.001) were lower after surgery. CONCLUSION: Metabolic surgery is superior to medical treatment for short-term remission of T2DM and comorbidities. Further RCTs should address the long-term effects on T2DM complications and mortality.

Non-erosive and uncomplicated erosive reflux diseases: Difference in physiopathological and symptom pattern.

AIM: To investigate differences in the physiopathological findings (manometry and pH monitoring) and symptoms between cases of non-erosive reflux disease (NERD) and erosive reflux disease (ERD) found positive at 24 h pH monitoring. METHODS: For a total of 670 patients who underwent 24 h pH monitoring, esophageal manometry and upper endoscopy were retrospectively evaluated, assessing the reflux symptoms, manometric characteristics of the lower esophageal sphincter (LES) and esophageal body and the presence or absence of esophagitis and hiatal hernia. Typical and atypical symptoms were also evaluated. For inclusion in the study, patients had to have NERD or ERD and be found positive on pH monitoring (NERD+). Patients with Gastroesophageal reflux disease (GERD) complicated by stenosis, ulcers or Barrett's esophagus were ruled out. RESULTS: 214 patients were involved in the study, i.e. 107 cases of NERD+ and 107 of ERD. There were no significant gender- or age-related differences between the two groups. The ERD group had more cases of hiatal hernia (P = 0.02) and more acid reflux, both in terms of number of reflux episodes (P = 0.01) and as a percentage of the total time with a pH < 4 (P = 0.00), when upright (P = 0.007) and supine (P = 0.00). The NERD+ cases had more reflux episodes while upright (P = 0.02) and the ERD cases while supine (P = 0.01). The LES pressure was higher in cases of NERD+ (P = 0.03) while the amplitude and duration of their esophageal peristaltic waves tended to be better than in the ERD group (P >0.05). The NERD+ patients presented more often with atypical symptoms (P = 0.01). CONCLUSION: The NERD+ patients' fewer reflux episodes and the fact that they occurred mainly while in the upright position (unlike the cases of ERD) may be two factors that do not favor the onset of esophagitis. The frequently atypical symptoms seen in patients with NERD+ need to be accurately evaluated for therapeutic purposes because patients with GERD and atypical symptoms generally respond only partially to medical and surgical treatments.