Our first experience in laparoscopic colorectal operations

Purpose: It has been almost 23 years since the first laparoscopic-assisted right hemicolectomy was done when the surgeons in our institution started doing laparoscopic colorectal operations mainly for malignant diseases. The aim of this communication was to present the beginning of the laparoscopic colorectal operations in St. Naum University Clinic of Surgical Diseases in Skopje, Macedonia.Material and methods: Twenty patients with colorectal adenocarcinoma were laparoscopically operated during the period from December 2012 to June 2013. Eleven of them were men and the rest women at a mean age of 58 years. Eight of them were rectal cancers, 3 were cancers of the rectosigmoid and the rest 9 were sigmoid adenocarcinomas. The patients were operated with 4 ports (sigmoid cancer) and 5 ports (rectum). Medial-to-lateral approach was used in all the cases. Tumour location dictated whether high or low ligation of inferior mesenteric artery (IMA) was done. Double stapler technique was applied for distal resection and anastomosis creation.Results: Mean operating time was 315 min. There were no perioperative and early postoperative deaths. One patient was reoperated early at the same operating day for mesenteric venous bleeding. There was one case of anastomotic leakage and a laparotomy was done with temporary colostomy. One unit of blood was given to five patients due to perioperative bleeding. Mean length of hospital stay was six days. Per oral nutrition started at day 2. Mean bowel function returned after 3,5 days. There were two seromas of the minilaparotomy wounds and no cases of surgical site infection. Selected cases of sigmoid and rectal cancer were suitable for beginning of learning the laparoscopic colorectal resection technique. The long operating time was understandable due to the steep learning curve. Conclusion: Laparoscopic colorectal surgery is safe and oncologically routine surgical method. It is widely used for many benign colorectal diseases, too. Prolonged learning of this technique should not be discouraging

Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining.

Non-homologous end joining (NHEJ) is one of the two principal damage repair pathways for DNA double-strand breaks in cells. In this review, we give a brief overview of the system including a discussion of the effects of deregulation of NHEJ components in carcinogenesis and resistance to cancer therapy. We then discuss the relevance of targeting NHEJ components pharmacologically as a potential cancer therapy and review previous approaches to orthosteric regulation of NHEJ factors. Given the limited success of previous investigations to develop inhibitors against individual components, we give a brief discussion of the recent advances in computational and structural biology that allow us to explore different targets, with a particular focus on modulating protein-protein interaction interfaces. We illustrate this discussion with three examples showcasing some current approaches to developing protein-protein interaction inhibitors to modulate the assembly of NHEJ multiprotein complexes in space and time

Public perceptions and expectations: disentangling the hope and hype of organoid research

Organoid technologies are rapidly advancing and hold great potential and hope for disease modeling and clinical translational research. Still, they raise a number of complex, ethical questions regarding their current and future use. Patient and public involvement is impor-tant in building public trust and helping to secure responsible conduct and valued innovations; nevertheless, research into patient and public perspectives on organoid technologies remains scarce. We report on a first public dialogue on organoid technologies through three cross-country deliberative workshops with a diverse group of stakeholders to identify their perceptions and concerns. Participants gener-ally support organoid technologies on the condition that responsible governance, ethical oversight, and sound informed consent procedures are in place. Yet, a broad set of potential concerns are identified, primarily concerning commercialization, healthcare access, and cerebral organoids. Participants' insights and recommendations can help inform researchers and ethics and policy bodies toward supporting responsible and ethical organoid approaches

Mechanistic differences in the transcriptional activation of p53 by 14-3-3 isoforms

p53 maintains genome integrity by initiating the transcription of genes involved in cell-cycle arrest, senescence, apoptosis and DNA repair. The activity of p53 is regulated by both post-translational modifications and protein–protein interactions. p53 that has been phosphorylated at S366, S378 and T387 binds 14-3-3 proteins in vitro. Here, we show that these sites are potential 14-3-3 binding sites in vivo. Epsilon (ε) and gamma (γ) isoforms required phosphorylation at either of these sites for efficient interaction with p53, while for sigma (σ) and tau (τ) these sites are dispensable. Further, σ and τ bound more weakly to p53 C-terminal phosphopeptides than did ε and γ. However, the four isoforms bound tightly to di-phosphorylated p53 C-terminal peptides than did the mono-phosphorylated counterparts. Interestingly, all the isoforms studied transcriptionally activated wild-type p53. σ and τ stabilized p53 levels in cells, while ε and γ stimulated p53-DNA binding activity in vitro. Overall, the results suggest that structurally and functionally similar 14-3-3 isoforms may exert their regulatory potential on p53 through different mechanisms. We discuss the isoform-specific roles of 14-3-3 in p53 stabilization and activation of specific-DNA binding

A phase II trial of preoperative chemotherapy with epirubicin, cisplatin and capecitabine for patients with localised gastro-oesophageal junctional adenocarcinoma

Preoperative cisplatin/fluorouracil is used for the treatment of localised oesophageal carcinoma. This phase II study aimed to assess the efficacy and safety of administering preoperative epirubicin/cisplatin/capecitabine (ECX). Patients with stage II or III oesophageal/gastro-oesophageal junctional adenocarcinoma from one institution received 4 cycles of ECX (epirubicin 50 mg m−2 day 1, cisplatin 60 mg m−2 day 1, capecitabine 625 mg m−2 b.i.d. daily) followed by surgery. The primary end point was the pathological complete response (pCR) rate based on a Simon two-stage design. Secondary end points included overall and progression-free survival (OS/PFS). Thirty-four patients were recruited: median age 60 years (range 41–81), 91% male, 97% PS 0/1, 80% T3, 68% N1. Thirty-one patients completed four ECX cycles. Grade 3/4 toxicities ⩾5% included neutropenia (62%), hand–foot syndrome (15%) and nausea/vomiting (9%). Thirteen out of 28 (46%) evaluable patients responded to chemotherapy by EUS (⩾30% reduction in maximal tumour thickness). Twenty-six out of 34 (76%) patients underwent resection (R0=73%, R1=27%). Post-operatively, two patients died within 60 days of surgery. The pCR rate was 5.9% (95% CI 0–14%) in the intent-to-treat population. According to the statistical design, this prompted early study termination. However, with a median follow-up of 34 months the median OS and 1- and 2-year survival rates were 17 months, 67 and 39% respectively. Median PFS was 13 months. Of the 14 relapsed patients, 10 presented with distant metastases. Preoperative ECX is feasible and well tolerated. Although associated with a low pCR rate, survival with ECX was comparable with published studies suggesting that pCR may not correlate with satisfactory outcome from preoperative chemotherapy for localised oesophageal adenocarcinoma

Current Treatment Strategies for Castration-Resistant Prostate Cancer

Prostate cancer is the most common cancer in men in United States and the fifth most common cancer in men in Korea. Although the majority of patients with metastatic prostate cancer initially respond to androgen deprivation therapy, almost all patients will eventually progress to develop castration-resistant prostate cancer (CRPC). Treatment options for CRPC remain limited. Prostate cancer was considered unresponsive to chemotherapy until the mid-1990s, when mitoxantrone combined with prednisone was shown to play a role in the palliative treatment of patients with CRPC. In 2004, two large randomized clinical trials demonstrated for the first time a small but significant survival advantage of docetaxel-based chemotherapy compared with mitoxantrone in patients with metastatic CRPC. Recently, cabazitaxel was shown to improve survival in patients with metastatic CRPC who progressed after docetaxel-based chemotherapy. Sipuleucel-T was also demonstrated to improve overall survival in patients with asymptomatic or minimally symptomatic metastatic CRPC. Along with mitoxantrone and docetaxel, cabazitaxel and sipuleucel-T are now approved for use in metastatic CRPC by the US Food and Drug Administration. There have been multiple early-phase clinical trials of various agents for the treatment of CRPC, and some are in phase III development. This review focuses on the key clinical trials of various treatment options of CRPC currently in use and under investigation

The phocein homologue SmMOB3 is essential for vegetative cell fusion and sexual development in the filamentous ascomycete Sordaria macrospora

Members of the striatin family and their highly conserved interacting protein phocein/Mob3 are key components in the regulation of cell differentiation in multicellular eukaryotes. The striatin homologue PRO11 of the filamentous ascomycete Sordaria macrospora has a crucial role in fruiting body development. Here, we functionally characterized the phocein/Mob3 orthologue SmMOB3 of S. macrospora. We isolated the gene and showed that both, pro11 and Smmob3 are expressed during early and late developmental stages. Deletion of Smmob3 resulted in a sexually sterile strain, similar to the previously characterized pro11 mutant. Fusion assays revealed that ∆Smmob3 was unable to undergo self-fusion and fusion with the pro11 strain. The essential function of the SmMOB3 N-terminus containing the conserved mob domain was demonstrated by complementation analysis of the sterile S. macrospora ∆Smmob3 strain. Downregulation of either pro11 in ∆Smmob3, or Smmob3 in pro11 mutants by means of RNA interference (RNAi) resulted in synthetic sexual defects, demonstrating for the first time the importance of a putative PRO11/SmMOB3 complex in fruiting body development

Molecular mechanisms of vaspin action: from adipose tissue to skin and bone, from blood vessels to the brain

Visceral adipose tissue derived serine protease inhibitor (vaspin) or SERPINA12 according to the serpin nomenclature was identified together with other genes and gene products that  were specifically expressed or overexpressed in the intra abdominal or visceral adipose tissue  (AT) of the Otsuka Long-Evans Tokushima fatty rat. These rats spontaneously develop visceral  obesity, insulin resistance, hyperinsulinemia and ‐glycemia, as well as hypertension and thus represent a well suited animal model of obesity and related metabolic disorders such as type  2 diabetes.  The follow-up study reporting the cloning, expression and functional characterization of  vaspin suggested the great and promising potential of this molecule to counteract obesity induced insulin resistance and inflammation and has since initiated over 300 publications, clinical and experimental, that have contributed to uncover the multifaceted functions and molecular mechanisms of vaspin action not only in the adipose, but in many different cells, tissues and organs. This review will give an update on mechanistic and structural aspects of vaspin with a focus on its serpin function, the physiology and regulation of vaspin expression, and will summarize the latest on vaspin function in various tissues such as the different adipose tissue depots as well as the vasculature, skin, bone and the brain

Suomalaisten matkailuhankkeiden tulostenseurannan mallityökalun kehittäminen

Opinnäytetyön tavoitteena oli kehittää matkailuhankkeiden tulostenseurannan mallityökalua. Työkalussa tulisi esille päättyneiden hankkeiden tulokset, tuotokset, hyvät käytänteet sekä onnistuneet ja epäonnistuneet kehittämistoimenpiteet. Selvitys suoritettiin matkailun kehittämisen koordinointitoimintaa varten. Aineistoina käytettiin päättyneiden matkailuhankkeiden loppuraportteja sekä matkailukehittäjille kohdennettua kyselyä. Tutkitut hankkeet olivat eri tyyppisiä ja teemaisia hankkeita eri puolilta Suomea. Tutkimusmenetelmänä käytettiin laadullista sisällönanalyysiä. Loppuraporttien tutkimisesta selvisi näiden sopimattomuus työkalun kehittämiseen haetun tiedon puutteen takia. Kyselyn kysymyksistä koostettiin kysymystaulukkoja, joihin haettiin vastauksia kyselyn kautta. Työn tuloksena syntyi taulukko, joka käsittelee kahta matkailuhanketta. Vastauksien saaminen kyselyyn osoittautui haasteeksi. Vaikka vastauksien määrä oli vähäinen, työkalun merkitys on selkeä. Ainoastaan kahdestakin vastauksesta selviää, että tulostenseurannan työkalussa on potentiaalia ja tämän hyöty hankkeiden tulosten levityksessä ja hyödyntämisessä on suuri. On oleellista kehittää työkalua edelleen ja kerätä mahdollisimman paljon vastauksia kyselyyn, jotta muodostuisi mahdollisimman kattava tulosten levitys- sekä hyödyntämistyökalu.The objective of the thesis was to develop a dissemination model tool for monitoring the results of tourism projects. The goal of the tool is to reveal the results and outcomes of the projects as well as their best practices, successes and failures regarding tourism development. This thesis was conducted with the aim to enhance the coordination of tourism development. The examined material consisted of final reports of projects and a questionnaire addressed to tourism developers. The examined projects were of different types and themes from all over Fin-land. The research method used was qualitative content analysis. Having examined the final re-ports, they proved to be unsuitable for creating the tool as they lacked the needed information. The questions from the prepared questionnaire became the basis for creating an evaluation table. The table was filled with the information from the answers to the questionnaire. The result of the thesis was a table covering two projects. Receiving answers to the questionnaire proved to be challenging. The number of received answers remained small. The meaning of the tool is, nevertheless, significant. The provided answers already made it clear that the tool has potential and its benefit in dissemination and exploitation of the results is substantial. It is crucial to further develop the tool and collect as much new data as possible in order to create a comprehensive dissemination and exploitation tool