Crk proteins activate the Rap1 guanine nucleotide exchange factor C3G by segregated adaptor-dependent and -independent mechanisms.

BACKGROUND: C3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by tyrosine phosphorylation and interaction with Crk adaptor proteins, whose expression is elevated in multiple human cancers. However, the molecular details of C3G activation and the interplay between phosphorylation and Crk interaction are poorly understood. METHODS: We combined biochemical, biophysical, and cell biology approaches to elucidate the mechanisms of C3G activation. Binding of Crk adaptor proteins to four proline-rich motifs (P1 to P4) in C3G was characterized in vitro using isothermal titration calorimetry and sedimentation velocity, and in Jurkat and HEK293T cells by affinity pull-down assays. The nucleotide exchange activity of C3G over Rap1 was measured using nucleotide-dissociation kinetic assays. Jurkat cells were also used to analyze C3G translocation to the plasma membrane and the C3G-dependent activation of Rap1 upon ligation of T cell receptors. RESULTS: CrkL interacts through its SH3N domain with sites P1 and P2 of inactive C3G in vitro and in Jurkat and HEK293T cells, and these sites are necessary to recruit C3G to the plasma membrane. However, direct stimulation of the GEF activity requires binding of Crk proteins to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Instead, phosphorylation primes C3G lowering the concentration of Crk proteins required for activation and increasing the maximum activity. Unexpectedly, optimal activation also requires the interaction of CrkL-SH2 domain with phosphorylated C3G. CONCLUSION: Our study revealed that phosphorylation of C3G by Src and Crk-binding form a two-factor mechanism that ensures tight control of C3G activation. Additionally, the simultaneous SH2 and SH3N interaction of CrkL with C3G, required for the activation, reveals a novel adaptor-independent function of Crk proteins relevant to understanding their role in physiological signaling and their deregulation in diseases. Video abstract.

GIST is not all that it seems.

We present a 41-year-old female who was admitted to our hospital with a history of 2-month epigastric pain and vomiting. Physical examination was normal. Upper gastrointestinal endoscopy showed a sessile submucosal tumor with central ulceration in the gastric body-antrum. Biopsies revealed a gastric mucosa without changes. Nevertheless, endoscopic ultrasound-guided biopsies showed interlacing bundles of spindle cells. The immunohistochemical study was negative for CD117 and smooth muscle actin and positive for S100 protein. A CT scan identified a heterogeneous mass in the stomach wall.

Idiopathic myointimal hyperplasia of the mesenteric veins, an uncommon cause of intestinal ischemia.

Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is an uncommon cause of intestinal ischemia. It was firstly described by Genta and Haggit in 1991. Only a few cases have been reported and it is difficult to know the true incidence.

Surgical acute abdomen and COVID-19 vaccination.

In response to the publication "Acute appendicitis, foreign bodies and COVID-19 vaccination: correspondence", we reviewed the association between acute surgical abdomen and COVID-19 vaccination.

Uncommon causes of acute appendicitis: foreign bodies in the cecal appendix.

A 50-year-old woman with a history of hysterectomy for endometrial cancer in 2015 visited because of abdominal pain for 1 week and fever simultaneous with her third dose of the COVID-19 vaccine. Physical examination revealed a mobile mass in the right iliac fossa, and laboratory testing showed C-reactive protein at 3 mg/dL, with no further changes. Ultrasound results were consistent with an appendiceal inflammatory mass, and a CT scan revealed an appendicolith as likely cause. The patient was subjected to laparoscopy, which found inside the mass a metallic piece (dental prosthesis) that perforated the appendiceal lumen at the mid portion of the appendix. Appendectomy was completed and the patient was discharged on the third day post-procedure.

Non-oclusive mesenteric ischemia as a complication of dialysis.

We present the case of a 69-year-old male ex-smoker, whose medical background included hypertension, chronic renal failure, atrial fibrillation anticoagulation, and chronic lower limb arterial ischemia. He suffered from abdominal pain associated with nausea and vomiting after a hemodialysis session. The analysis showed C-reactive protein at 7 mg/L, 14,500 leukocytes with neutrophilia, and lactate at 2.8. A computerized axial tomography (CAT) scan was performed and portal pneumatosis as well as a distal ileum segment with intestinal pneumatosis were observed, which was compatible with non-occlusive mesenteric ischemia.

Lumen-apposing metal stent deployment failure.

Endoscopic ultrasound-guided transmural drainage has become a first-line therapy for pancreatic fluid collections (1). The appearance of lumen-apposing metal stents has resulted in an authentic revolution, due to their efficacy (clinical success rate of 93%) and easy deployment (technical success rate of 98%) (2). They are associated with a shorter procedure time, lower risk of migration and a wider lumen, which could provide a more effective drainage (3). We report the case of a 78-year-old male who developed an infected pancreatic pseudocyst as a late complication of an acalculous severe acute pancreatitis. An endoscopic ultrasound-guided transmural drainage was performed after a failed computed tomography-guided percutaneous drainage with placement of a pig-tail catheter. A gastrocystic fistula was created and an AxiosTM lumen-apposing metal stent (Boston Scientific; Massachusetts, United States) was inserted. Nevertheless, it remained lodged in the pancreatic pseudocyst at the time of deployment. A computed tomography scan confirmed stent placement inside the collection (Figure 1). After endoscopic balloon dilatation of gastrocystic fistulous tract, removal was unsuccessful with proximal traction of the lumen stent flange using biopsy forceps. Surgical treatment was decided and a gastrotomy was performed, the fistula was identified in the posterior gastric wall and the stent was removed. Endoscopic ultrasound-guided transmural drainage of pancreatic fluid collections using lumen-apposing metal stents is a safe procedure. However, it is not exempt of complications such as stent migration, bleeding, gastrointestinal perforation and air embolism (4). Technical failure of lumen-apposing metal stents deployment is a rare complication that may require surgical treatment if endoscopic removal is not possible.

Twisting of sleeve gastrectomy: two ways of clinic presentation.

Laparoscopic sleeve gastrectomy is an increasingly widespread bariatric surgical technique thanks to its good outcomes and apparent simplicity. However, complications may arise, including hemorrhage, gastric fistula, and stenosis, which can be either organic or functional. Functional stenosis is caused by gastric tube twisting. We present two cases of patients who underwent laparoscopic sleeve gastrectomy and who were subsequently diagnosed with gastric twisting. Both cases required conversion to laparoscopic gastric bypass. Accompanying symptoms may vary but they commonly include early satiety, epigastric pain associated with food intake, gastroesophageal reflux and early vomiting. Although diagnose is mainly clinical, it requires high suspicion since endoscopy and gastrointestinal studies are not conclusive. The principal therapeutic options are endoscopic dilatations, serotomy and conversion to gastric bypass.

Esophageal perforation by a Sengstaken balloon.

Iatrogenic esophageal perforations are rare but associated with a high morbidity and mortality. Secondary to placing a Sengstaken ballon are even more extraordinary because of the infrequency which this measure is used to control upper gastrointestinal bleeding. Therefore, we think it is of interest to communicate this complication, to remember the need to check the correct placement of the Sengstaken ballon before insufflation, since it would help further decrease this complication.

Acute abdomen from duodenal diverticulitis. A case report.

Duodenal diverticula are a rare, usually asymptomatic clinical condition. When a complication arises clinical suspicion is key for the diagnosis. On occasion these patients receive a delayed diagnosis and undergo inadequate medical therapy. We report the case of a patient with evidence of duodenal diverticulitis in association with gallbladder inflammation by contiguity, as well as his diagnosis and management.

Small bowel mesenchymal tumors: description of two unusual cases.

We present two cases of intestinal ileal GIST who developed complications of nonspecific signs and required to be operated urgently, providing unusual images of tumors because of its characteristics.

Intestinal endometriosis. Our experience.

Intestinal endometriosis is defined as a bowel infiltration by ectopic endometrial tissue. The prevalence is 3-37% of all women affected by endometriosis. Rectosigmoid colon is the most frequent location (70-93%), followed to ileocecal region, appendix and other colon and small bowel segments. Intestinal endometriosis usually is asymptomatic. Often it is only diagnosed during surgery for other reasons. The symptoms frequently are nonspecific, although it may appear as an acute abdominal pain. Clinical history, physical examination and image techniques are necessary for the diagnosis. The choice of the operative technique depends on the clinical presentation and on the fertility wishes of the patient. Laparotomy and laparoscopy are equally effective, but laparoscopic approach is preferred. We present 17 cases of patients from our Hospital diagnosed with intestinal endometriosis, from 2006 to 2015.

Cost-effectiveness analysis of sofosbuvir-based regimens for chronic hepatitis C.

BACKGROUND: A new scenario of therapy for chronic hepatitis C (CHC) is being established with the approval of sofosbuvir (SOF). OBJECTIVE: To estimate the cost-effectiveness of SOF-based regimens approved in the Summary of Product Characteristics (SmPC) versus the standard of care for different genotypes and patient populations (naive or pretreated). METHODS: A Markov model simulating CHC progression was used to estimate disease treatment costs and effects over patients' lifetimes, from the Spanish National Public Healthcare System perspective. Different therapeutic options were analysed for genotypes 1, 2 and 3 in naive population and for genotype 2 and 3 pretreated patients, according to data obtained from clinical trials. A one-way sensitivity analysis was performed to evaluate the uncertainty of certain parameters: treatment starting age, transition probabilities, drug costs and discount rate. A probabilistic sensitivity analysis was also carried out. RESULTS: For the naive population, the option SOF+pegylated-interferon-α (pIFN)+ribavirin (RBV) for 12 weeks recorded in SmPC for genotype 1 and 3 versus pIFN+RBV for 24 weeks estimated an incremental cost-effectiveness ratio (ICER) below the €40,000/quality-adjusted life-year (QALY) benchmark. For the pretreated population, SOF triple therapy reached an ICER on the threshold limit for genotype 3. Other options included in SmPC for different genotypes exceeded the accepted efficiency limit in our setting. CONCLUSIONS: The options that included SOF+RBV+pIFN in a 12-week course regimen fell below the efficiency threshold considered in our setting. IFN-free regimens administered for 24 weeks reached figures over the benchmark of €40,000/QALY.

Perforación traqueal diferida tras cirugía tiroidea en un paciente con radioterapia cervical.

Tracheal perforation is a rare complication of thyroid surgery. A 36-year-old man with previous neck radiotherapy due to a nasopharyngeal cancer. After right hemithyoidectomy and isthmusectomy, the patient presented a tracheal perforation. The diagnosis was confirmed with computed tomography and bronchoscopy. A conservative management was performed with drainage and antibiotic therapy, and the evolution was satisfactory. If recognized at the time of the surgery, perforations should be closed primarily. Delayed perforations will be treated with an emergency surgery or conservatively depending on the clinical situation of the patient.

La perforación traqueal es una rara complicación de la cirugía tiroidea. Varón de 36 años con antecedente de radioterapia cervical por una neoplasia de cavum sometido a hemitiroidectomía derecha e istmectomía que durante el posoperatorio presentó una perforación traqueal confirmada por tomografía computarizada y broncoscopia. Se realizó manejo conservador con drenaje y antibioticoterapia, evolucionando de forma favorable. Las perforaciones identificadas durante la cirugía deben ser reparadas intraoperatoriamente, mientras que las diferidas se tratarán de forma quirúrgica urgente o de manera conservadora en función de la situación clínica del paciente.

Transanal irrigation as a therapeutic option for patients with incontinence and severe chronic constipation refractory to first-line treatment.

INTRODUCTION: The aim is to evaluate the utility of transanal irrigation such as treatment of incontinence and severe chronic constipation which is refractory to first-line therapy, and to assess its impact into the symptomatology and quality of life. METHODS: Observational retrospective study of patients with incontinence and chronic constipation that had initiated transanal irrigation in two hospitals of the region. We collect sociodemographic variables, comorbidity, previous treatments, tests, parameters and incidences during the irrigation, and punctuation in the Cleveland Clinic Incontinence and Constipation Scores and EuroQol-5D Quality Of Life Scale before and after the treatment. RESULTS: 40 patients, 20 with incontinence and 20 with chronic constipation. After an average period of 9 months of treatment, in 14 patients with incontinence we have observed a mean clinical improvement of 7,45 points before-after treatment measured with Cleveland Clinic Incontinence Score, and a mean improvement of 23 points in their quality of life before-after treatment measured with EQ5D Scale (P < .001); and in 16 patients with constipation a mean clinical improvement of 7,6 points before-after treatment measured with Cleveland Clinic Constipation Score, and a mean improvement of 31,5 points in their quality of life before-after treatment measured with EQ5D Scale (P < .001). CONCLUSIONS: Transanal irrigation is an effective therapy for patients with incontinence and chronic constipation that are refractory to first-line therapies. It's an easy, self-administered and safe procedure. When the patient learns how to use it, the symptomatology and quality of life are improved.

[Non-obstructive enterolithiasis: report of two cases]. / Enterolitiasis no obstructiva: presentación de 2 casos.

Enterolithiasis, or coprolithiasis, stones formed mainly in the intestine, is uncommon in humans and is generally associated with intestinal stasis. This entity is highly common in some animals, such as horses. Enterolithiasis is usually asymptomatic but may lead to intestinal occlusion and should be considered as a possible cause of this event. We report two cases of enterolithiasis, in which the diagnosis was established by simple abdominal radiography and computed tomography. Although both patients had factors favoring the development of enterolithiasis, a genetic substrate predisposing them to this uncommon clinical entity cannot be excluded.

Postoperative Diet with an Oligomeric Hyperproteic Normocaloric Supplement versus a Supplement with Immunonutrients in Colorectal Cancer Surgery: Results of a Multicenter, Double-Blind, Randomized Clinical Trial.

(1) Background: For normo-nourished colorectal cancer patients, the need for immunonutrients after elective surgery is not known. (2) Methods: Multicenter, randomized, double-blind, phase III clinical trial comparing the postoperative diet with 200 mL oligomeric hyperproteic normocaloric (OHN; experimental arm) supplement vs. 200 mL immunonutritional (IN) (active comparator) supplement twice a day for five days in 151 normo-nourished adult colorectal-resection patients following the multimodal rehabilitation ERAS protocol. The proportions of patients with complications (primary outcome) and those who were readmitted, hospitalized for <7 days, had surgical site infections, or died due to surgical complications (secondary outcome) were compared between the two groups until postoperative day 30. Tolerance to both types of supplement and blood parameters was also assessed until day 5. (3) Results: Mean age was 69.2 and 84 (58.7%) were men. Complications were reported in 41 (28.7%) patients and the incidence did not differ between groups (18 (25%) vs. 23 (32.4%) patients with OHN and IN supplement, respectively; p = 0.328). No significant differences were found for the rest of the variables. (4) Conclusions: IN supplement may not be necessary for the postoperative recovery of colorectal cancer patients under the ERAS regimen and with normal nutritional status at the time of surgery.