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PM742 ( 1 ), a new chemical entity, has been isolated from the sponge Discodermia du Bocage collected in the Pacific Ocean. This compound showed strong in vitro cytotoxicity against several human tumor cell lines as well as a tubulin depolymerization mechanism of action, which led us to conduct an extensive Structure-Activity-Relationship study through the synthesis of different analogs. As a result, a derivatively named PM534 ( 2 ) is currently in its first human Phase I clinical trial. Herein, we present a comprehensive review of the isolation, structural elucidation, and antitumor activities of the parent compound PM742.

Targeting microtubules is the most effective wide-spectrum pharmacological strategy in antitumoral chemotherapy, and current research focuses on reducing main drawbacks: neurotoxicity and resistance. PM534 is a novel synthetic compound derived from the Structure-Activity-Relationship study on the natural molecule PM742, isolated from the sponge of the order Lithistida , family Theonellidae , genus Discodermia (du Bocage 1869). PM534 targets the entire colchicine binding domain of tubulin, covering four of the five centers of the pharmacophore model. Its nanomolar affinity and high retention time modulate a strikingly high antitumor activity that efficiently overrides two resistance mechanisms in cells (detoxification pumps and tubulin βIII isotype overexpression). Furthermore, PM534 induces significant inhibition of tumor growth in mouse xenograft models of human non-small cell lung cancer. Our results present PM534, a highly effective new compound in the preclinical evaluation that is currently in its first human Phase I clinical trial.

Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation., Competing Interests: AG reports honoraria (Clovis, MSD, AstraZeneca, GSK, PharmaMar and Roche) and travel/accommodation/expenses (Merck Sharp and Dohme, PharmaMar, Roche, Eisai, Pfizer, Pierre-Fabre and Tesaro-A GSK Company), outside the submitted work. MM-D is employee and shareholder of PharmaMar S.A. (Madrid, Spain). AR reports honoraria and advisory/consultancy (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, Amgen), research grant/funding to his institution (Eisai, PharmaMar, Roche), travel/accommodation/expenses (AstraZeneca, Tesaro: A GSK Company, PharmaMar, Roche), and speakers bureau (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar), outside the submitted work. MMe reports honoraria (MSD, AstraZeneca and GSK), research grant/funding to her institution (Eisai and PharmaMar), travel/accommodation/expenses (AstraZeneca, GSK, PharmaMar, Roche and Pfizer), outside the submitted work. The authors declare that this study received funding from PharmaMar S.A. (MM-D). The funder had the following involvement with the study: performed immunofluorescence experiments and reviewed draft preparation., (Copyright © 2022 Heredia-Soto, Escudero, Miguel, Ruiz, Gallego, Berjón, Hernández, Martínez-Díez, Zheng, Tang, Hardisson, Feliu, Redondo and Mendiola.)

Background: Through several not-fully-characterised moonlighting functions, translation elongation factor eEF1A2 is known to provide a fitness boost to cancer cells. Furthermore, eEF1A2 has been demonstrated to confer neoplastic characteristics on preneoplastic, nontumourigenic precursor cells. We have previously shown that eEF1A2 is the target of plitidepsin, a marine drug currently in development for cancer treatment. Herein, we characterised a new signalling pathway through which eEF1A2 promotes tumour cell survival., Methods: Previously unknown binding partners of eEF1A2 were identified through co-immunoprecipitation, high-performance liquid chromatography-mass spectrometry and proximity ligation assay. Using plitidepsin to release eEF1A2 from those protein complexes, their effects on cancer cell survival were analysed in vitro., Results: We uncovered that double-stranded RNA-activated protein kinase (PKR) is a novel eEF1A2-interacting partner whose pro-apoptotic effect is hindered by the translation factor, most likely through sequestration and inhibition of its kinase activity. Targeting eEF1A2 with plitidepsin releases PKR from the complex, facilitating its activation and triggering a mitogen-activated protein kinase signalling cascade together with a nuclear factor-κB-dependent activation of the extrinsic apoptotic pathway, which lead to tumour cell death., Conclusions: Through its binding to PKR, eEF1A2 provides a survival boost to cancer cells, constituting an Achilles heel that can be exploited in anticancer therapy.

PM060184 belongs to a new family of tubulin-binding agents originally isolated from the marine sponge Lithoplocamia lithistoides. This compound is currently produced by total synthesis and is under evaluation in clinical studies in patients with advanced cancer diseases. It was recently published that PM060184 presents the highest known affinities among tubulin-binding agents, and that it targets tubulin dimers at a new binding site. Here, we show that PM060184 has a potent antitumor activity in a panel of different tumor xenograft models. Moreover, PM060184 is able to overcome P-gp mediated resistance in vivo, an effect that could be related to its high binding affinity for tubulin. To gain insight into the mechanism responsible of the observed antitumor activity, we have characterized its molecular and cellular effects. We have observed that PM060184 is an inhibitor of tubulin polymerization that reduces microtubule dynamicity in cells by 59%. Interestingly, PM060184 suppresses microtubule shortening and growing at a similar extent. This action affects cells in interphase and mitosis. In the first case, the compound induces a disorganization and fragmentation of the microtubule network and the inhibition of cell migration. In the second case, it induces the appearance of multipolar mitosis and lagging chromosomes at the metaphase plate. These effects correlate with prometaphase arrest and induction of caspase-dependent apoptosis or appearance of cells in a multinucleated interphase-like state unrelated to classical apoptosis pathways. Taken together, these results indicate that PM060184 represents a new tubulin binding agent with promising potential as an anticancer agent., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Trabectedin and Zalypsis are two potent anticancer tetrahydroisoquinoline alkaloids that can form a covalent bond with the amino group of a guanine in selected triplets of DNA duplexes and eventually give rise to double-strand breaks. Using well-defined in vitro and in vivo assays, we show that the resulting DNA adducts stimulate, in a concentration-dependent manner, cleavage by the XPF/ERCC1 nuclease on the strand opposite to that bonded by the drug. They also inhibit RNA synthesis by: (1) preventing binding of transcription factors like Sp1 to DNA, and (2) arresting elongating RNA polymerase II at the same nucleotide position regardless of the strand they are located on. Structural models provide a rationale for these findings and highlight the similarity between this type of DNA modification and an interstrand crosslink., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: the accuracy of preoperative endorectal ultrasound in the status evaluation of lymph nodes is around 50-70%, with a lack of eco-morphological patterns of clinical use. Since, accurate local staging is of great value in prognosis and decision-making we decided to analyze the referenced eco-morphological parameters in a try to find a proper predictive tool of clinical help that could improve the accuracy of rectal ultrasound., Material and Method: the resected specimens of 24 patients that were operated on by radical surgery because rectal cancer, without preoperative radiotherapy were suspended in warm water and ultrasound scanned (360º circular probe with a transducer of 10 Mhz). All suspicious nodes were recorded and marked for the definitive histological report., Results: from the 24 specimens, 318 nodes were imaged(210 benign and 100 involved). All ultrasound parameters analysed were significant but only lobulation, echogenicity and hilar reflection were independent values. An score system was design with the addition of all parameters that showed a sensitivity of 98%and specificity of 99,1%., Conclusions: our study shows that a careful study of ultra-sound lymph node images can get a high level of accuracy and better help in tailoring the treatment of any particular case.

Introduction: Biliopancreatic diversion by Scopinaro (BD) is a mixed (malabsortive and restrictive) bariatric technique that is successful in achieving long lasting weight lost in super obese patients. In fact, the diarrhoea (steatorrhea) that is expected after any malabsortive technique can sometimes cause significant nutritional changes and anal disease: these patients are frequently referred to our coloproctology outpatient clinic due to haemorrhoids, fissures, anal sepsis and fistula basically due to changes in quality and quantity of their faeces. The aim of this paper is to find out not only the prevalence of anal disease in our series of super obese surgical patients but also to compare the incidence between the two surgical techniques we perform in our department., Material and Method: We analyzed 263 consecutive patients operated on BD of Scopinaro (50-200 cm) and modified-BD (75-225 cm) in our Department. Patients who had previously suffered from anal surgery were excluded., Results: There were 45 patients (18%) who suffered from anal problems of which 38 cases (84.4%) were BD-S and only 7 cases with BD-M complained of anal disorders (p < 0.05). Overall, at the 18th month review, the mean number of motions per day was 3.5 (range, 1-15). Patients with BD-S had 5 motions per day as a mean. The mean number of motions for BD-M was 2. The frequency order of anal pathology observed was: anal fissure, haemorrhoids, abscess and fistula., Conclusions: Higher incidence of anal pathology after BD of Scopinaro is another factor to take into account to avoid performing classic Scopinaro BD as opposed to modified BD for the treatment of morbid super obesity. It is mandatory to be conservative when facing anal problems in these patients, and firstly we must modify eating habits and the nutritional status. Surgery must be highly respectful to anal sphincters to avoid incontinence.

Background: Sometimes Graveś disease (GD) can appear in association with thyroid nodules, which seems to increase the risk of carcinoma. In this article, we try to establish clinical characteristics, diagnostic means and appropriate treatment for Graves patients with co-existent nodules., Method: A retrospective study was made of 153 consecutive patients who underwent operation for GD between 1967 and 2000. Each patient was subject to a regular protocol including physical examination, diagnostic test, total or subtotal thyroidectomy and follow-up in the long term with the purpose of making a valuation of the postsurgical morbidity, evolution and relapses. Data were processed through computing in order to get the statistical information., Results: 28.1% of GD had thyroid nodules and carcinoma was diagnosed in four patients (9.3%), all of them belonging to papillary variety. Surgery consisted of 57 subtotal thyroidectomies (37.3%) and 94 total thyroidectomies. Parathyroid and recurrent morbidity was established in 4.6 and 3.9%, respectively, a year later since the operation, though it had a strong tendency to decrease from 1980. 96% of cases showed no relapse., Conclusions: Nodular GD is very common in our setting, especially in Graveś patients with late beginning who wait for ages until they are undergone surgery. Initial treatment should be by means of braking therapy with antithyroid drugs and clinical, cytologic and ultrasonographic control. Surgery would be advised, from the outset or during the follow-up, in view of either any suspicion about cancer or presence of local growth. The procedure of choice is total thyroidectomy performed with low morbidity.

Background: Operations for morbid obesity that are effective in inducing weight loss improve blood pressure, glycemic control and dyslipidemia. Our purpose was to study the effectiveness of VBG in improving hypertension, diabetes and dyslipidemias in morbidly obese patients., Methods: Retrospective analysis of a cohort of 80 morbidly, obese patients was conducted. Characteristics of patients were: mean age 37 years; gender: women 65, men 15; mean initial BMI 49.5 kg/m2; follow-up > 5 years in 52 patients. Blood pressure, cholesterol and triglyceride levels and glycemia were assessed preoperatively and 1, 3, 6, 12, 18 months and every year after VBG., Results: Hypertension resolved in 65.5% of patients (38 of 58), serum cholesterol level became normal in 34.28% of patients (12 of 35), triglyceride level became normal in 77.77% (7 of 9) and diabetes resolved in 55.55% (5 of 9)., Conclusion: Weight loss induced by VBG improves blood pressure, triglyceride levels and glycemia. The beneficial changes occur early in the postoperative period and last 5 years or more, despite of the trend to regain some weight. Improvements in risk factors were greater in patients with higher preoperative values.

Objective: To present normal images and sonographic variants of the anal canal to be used as reference for the study of sphincter and anal canal abnormalities., Material and Methods: Sixty subjects without known anal canal disease were studied by means of anal endosonography. Subject were divided according to age in two groups (up to 50 years and more than 50 years). All of them underwent an outpatient study with B&K medical ultrasound 2,003 scanner and 1,850 multifrequency transducer., Results: Four layers can be sonographically identified in the anal canal: an inner hyperechoic layer which is the submucosa, a second hypoechoic layer which is the internal sphincter, a third one which is a longitudinal muscle and the outer hyperechoic layer which is the external sphincter and the only to be found in the low anal canal. In people older than 50 years, both sphincters were significantly thicker (0.3-0.5 mm). At the high anal canal 40% of women presented an anterior gap in the external anal sphincter., Conclusions: Anal endosonography allows an easy division in high-, mid-, and low anal canal. In some women there is a gap at the mid-high anal canal that must be taken into account in order to avoid diagnostic errors. An internal sphincter thickness greater than 3.5 mm should be considered abnormal at any sex or age.

Objective: To describe two cases of adrenal pseudocyst that presented as acute abdomen and shock., Methods: Two cases of adrenal pseudocyst are presented: one patient was a 69-year-old woman who presented with shock and pain in the left hypochondrium and the other was a 23-year-old woman who complained of dizziness and pain in the left hypochondrium., Results: US and CT evaluation showed a heterogeneous cystic mass. Blood analysis showed low hematocrit and hemoglobin levels. Surgical resection of the retroperitoneal cystic mass was performed. The pathological analysis disclosed an adrenal pseudocyst., Conclusions: Adrenal pseudocyst is an uncommon lesion that infrequently causes symptoms and rarely presents as acute abdomen. Ultrasound and CT are the most useful diagnostic imaging methods. Treatment is by surgery if the lesion is large and symptomatic, if it cannot be clearly distinguished from a tumor, and if massive hemorrhage occurs.

Objective: To report our results with local excision by transanal endoscopic microsurgery (TEM) to treat 42 cases of rectal lesions (29 adenomas and 13 carcinomas)., Methods: Prospective, descriptive study. Sex distribution: 55% men, 45% women, mean age 65 years (range: 17-84 years)., Symptoms: rectal bleeding 67%, diarrhea 23%., Surgical Technique: mucosectomy 6 cases, full-thickness excision 36 cases. Average follow-up: 11 months (range: 1-36 months)., Results: We analyzed operating time (average 85 min; range: 25-180 min), bleeding (average 100 ml, range 10-350 ml), distance of the tumor from the anal verge (lower tumor margin: mean, 8.8 cm; range, 1-20 cm; distal tumor margin: mean, 12.9 cm; range, 5-22 cm), tumor size (mean, 3.9 cm; range, 2-10 cm), postoperative hospital stay (average, 4 days; range, 2-15 days), morbidity (hemorrhage 1 case; perforation, 1 case), mortality (0) and follow-up (temporary incontinence to flatus in 6 cases, 1 recurrence of carcinoma treated with abdominoperineal resection, 2 recurrences of adenoma and 2 new adenomas)., Conclusions: TEM is a safe technique for the treatment of rectal lesions. Low morbidity and recurrence rates and short hospital stays make TEM a procedure of choice when local rectal surgery is indicated.

Objectives: endorectal ultrasound (EUS) is currently accepted as the best technique for the preoperative study of patients with rectal tumors, and surgical decisions depend increasingly on EUS staging. The main pitfalls in staging rectal tumors are over- or understaging as well as errors in imaging lymph nodes. Being aware of such errors and their causes may help to improve the overall results. The aim of the present study was to evaluate the accuracy of EUS in staging rectal neoplasms, and to study potential sources of error., Methods: from May 1996 to December 1998, 120 patients with rectal tumors were studied preoperatively by EUS. The uTNM classification described by Hildebrandt and coworkers was used. The EUS findings were compared prospectively with the results of pathological examination. When there was no correlation, both the specimen and the EUS findings were carefully reviewed to look for potential sources of error., Results: 41 out of 120 patients were classified as uT1, 10 as uT2, 60 as uT3 and 9 out of 120 as uT4. 31 patients had positive lymph nodes (uN1). On comparing these data with the results of the pathological report, we found 90% accuracy in staging rectal wall penetration, and 70% accuracy in the diagnosis of lymph nodes. Errors were due basically to technical problems, characteristics of the tumor itself, and difficulties in staging lymph nodes., Conclusions: it is important to identify the potential source of errors as well as the current limitations of EUS to improve the overall results with this technique.

When overweight surpasses 100% of the ideal weight, morbid obesity, the obese patients is condemned to a complete inability to work, social and sexual inability, and shall suffer from an increase in its morbidity and mortality. This depends to a large degree on the additions to the obesity of insulin resistance, carbohydrates intolerance, hypertriglyceridemia, hypercholesterolemia, and arterial hypertension, all of which is enveloped in a atmosphere of neuroendocrine alterations. An efficient method of treating this syndrome is weigh loss. Medical treatments have not achieved prolonged weight losses during long periods in morbid obese patients, which is a reason for surgery to try and propose new lines of treatment for these patients. The purpose of our study is to examine the effect of weight loss in 100 patients treated with vertical gastroplasty, on the metabolic disorders (triglycerides, cholesterol, glucose) and the arterial hypertension, which are considered to be risk factors in the mortality associated with morbid obesity. Our results indicate that the weight loss modified the metabolic conditions of the patients, with there being a decrease of the levels of triglycerides, cholesterol, glucose, and arterial pressure, after 6 to 12 months after the weigh loss.

There are many published experimental studies which attempt to explain certain aspects of satiety, but only very few treat this problem as a whole, synthesizing concepts. At present, the understanding of the mechanisms of satiety is extremely interesting for the study and application of medical or surgical anti-obesity treatments.

Cells that produce somatostatin are widely distributed throughout the digestive tube. They are found in the stomach, small bowel, large bowel and pancreas. The authors used 54 Wistar rats, with an approximate weight of 300 gr, to evaluate the possible variations of the D cell population in isolated and functional intestinal segments, using jejuno-ileal bypass as a model. Rats were divided into three groups, a control group and two groups in which simple derivation techniques were performed following the techniques of Payne and DeWind, and Scott. Rats were sacrificed after 7, 30 and 90 days in subgroups of six animals. Macroscopic, microscopic and ultrastructural studies were carried out. Cells were specifically stained using immunocytochemical techniques (PAP). The corresponding values of the mucous areas were obtained using a computerized image analyzer (Quantimet 800) and then the number of D cells per mm2 mucosa was calculated. The results show a decrease in the number of D cells per mm2 of mucosa in the functional intestinal segments and degranulation of these cells, coinciding with the existence of large areas of rough endoplasmic reticulum (sign of cellular hyperactivity).

This was a multicenter study corresponding to 40 services. For each patient, a card containing 90 questions was filled out. At the same time we sent a personal survey card with 11 criteria questions. Our cases corresponded to 805 patients, 457 males and 348 females. The highest frequency was between 50-80 years. The therapeutic methods most often used were: drainage plus Hartmann, 37.1%; drainage plus colostomy, 24.9%; resection and anastomosis without colostomy, 12.45%, and with colostomy, 5.11%; drainage plus exteriorization, 5.98%, and conservative, 4.6%. We studied the morbimortality correlation according to different anatomoclinical groups and techniques used. The results were nonsignificant for mortality and statistically significant for evisceration, eventration, diffuse peritonitis, upper gastrointestinal bleeding, anastomotic dehiscence and type of anastomosis, manual or instrumental.