[Distal pancreatectomy with resection of the celiac trunk, right or left hepatic artery without arterial reconstruction (extended DP-CAR)]. / Distal'naya rezektsiya podzheludochnoi zhelezy s rezektsiei chrevnogo stvola vmeste s pravoi ili levoi pechenochnoi arteriei bez arterial'noi rekonstruktsii (rasshirennaya DP-CAR).

OBJECTIVE: To evaluate safety and postoperative outcomes of DP-CAR with resection of one of the lobar hepatic arteries without arterial reconstruction (extended DP-CAR). MATERIAL AND METHODS: Perioperative data and survival after 7 extended DP-CARs R0 were retrospectively analyzed. Arterial blood flow in the liver was assessed using intraoperative ultrasound and postoperative CT angiography. RESULTS: Among 40 DP-CARs, resection of left or right hepatic artery was performed in 7 cases of aberrant anatomy including 1 case of portal vein resection. Mortality and ischemic complications were not observed. The main source of blood supply to the «devascularized¼ liver lobe was interlobar communicating artery or the arcade of the lesser curvature of the stomach. Incidence of pancreatic fistula was 44%, mean blood loss - 230 (100-650) ml, surgery time - 259 (195-310) min, mean hospital-stay - 14 (9-26) days. Median survival of patients with pancreatic ductal adenocarcinoma was 25 months after combined treatment. Three patients died after 26, 28 and 77 months. Other patients are alive without progression for 109, 24, 23 and 12 months after therapy onset. CONCLUSION: Extended DP-CAR is advisable and safe procedure if reliable intraoperative control of liver and stomach blood supply is ensured.

[Resectable periampullary tumor in patients with previous pancreatitis. What type of surgical procedure to choose?] / Rezektabel'naya periampulyarnaya opukhol' u patsienta, perenesshego ostryi pankreatit. Kakuyu operatsiyu vybrat'?

OBJECTIVE: To evaluate the early outcomes of radical surgical treatment of patients with resectable periampullary tumors and previous acute pancreatitis (AP). MATERIAL AND METHODS: A retrospective analysis included 9 patients. AP was diagnosed in all patients at different times of preoperative period (post-manipulative AP in 7 cases, alcoholic AP in 2 cases). Pancreaticoduodenectomy was performed in 5 patients, total pancreatectomy (TP) - in 4 patients. RESULTS: Severe postoperative complications occurred in 3 patients after pancreaticoduodenectomy. There were no complications after TP. All complications after pancreaticoduodenectomy were associated with a pancreatic stump that required urgent surgical interventions. Three patients died from surgical complications. All postoperative deaths were observed after pancreaticoduodenectomy. CONCLUSION: TP may be a safer surgical option compared to pancreaticoduodenectomy in patients with resectable periampiullary tumors and preoperative AP.

Multifunctional Complexes Based on Photoluminescent Upconversion Nanoparticles for Theranostics of the HER2-Positive Tumors.

Combining diagnostic and therapeutic functions in one agent is a promising strategy in the development of personalized approaches to the treatment of cancer. The opportunity to combine diagnostics and therapy appeared with the development of nanobiotechnologies and was realized in the concept of theranostics. To date, a number of promising agents based on nanomaterials capable of diagnosing, targeted therapeutic effects, and monitoring the response of tumor cells were obtained within the approach of theranostics. In this work, a new type of theranostic complexes based on upconversion nanoparticles coated with polyethylene glycol and functionalized with the DARPin-LoPE recombinant targeted toxin was developed. Selective binding of complexes to human breast adenocarcinoma cells overexpressing the HER2 receptor and specific toxicity to them were shown.

Outcomes of octogenarians with esophageal cancer: an analysis of the National Cancer Database.

The optimal treatment of esophageal cancer in octogenarians is controversial. While the safety of esophagectomy has been demonstrated in elderly patients, surgery and multimodality therapy are still offered to a select group. Additionally, the long-term outcomes in octogenarians have not been thoroughly compared to those in younger patients. We sought to compare the outcomes of esophageal cancer treatment between octogenarians and non-octogenarians in the National Cancer Database (2004-2014). The major endpoints were early postoperative mortality and long-term survival. A total of 107,921 patients were identified [octogenarian-16,388 (15.2%)]. Compared to non-octogenarians, octogenarians were more likely to be female, of higher socioeconomic status, and had more Charlson comorbidities (p < 0.001 for all). Octogenarians were significantly less likely to undergo esophagectomy (11.5% vs. 33.3%; p < 0.001) and multimodality therapy (2.0% vs. 18.5%; p < 0.001), a trend that persisted following stratification by tumor stage and Charlson comorbidities. Both 30-day and 90-day mortality were higher in the octogenarian group, even after multivariable adjustment (p ≤ 0.001 for both). Octogenarians who underwent multimodality therapy had worse long-term survival when compared to younger patients, except for those with stage III tumors and no comorbidities (HR: 1.29; p = 0.153). Within the octogenarian group, postoperative mortality was lower in academic centers, and the long-term survival was similar between multimodality treatment and surgery alone (HR: 0.96; p = 0.62). In conclusion, octogenarians are less likely to be offered treatment irrespective of tumor stage or comorbidities. Although octogenarians have higher early mortality and poorer overall survival compared to younger patients, outcomes may be improved when treatment is performed at academic centers. Multimodality treatment did not seem to confer a survival advantage compared to surgery alone in octogenarians, and more prospective studies are necessary to better elucidate the optimal treatment in this patient population.

Removal of the Translocation Domain and the Furin Cleavage Site Decreases the Relative Hepatotoxicity of the Targeted Antitumor Toxins.

Targeted toxins are promising anticancer agents that allow selectively destroying cancer cells due to the increased content of onco-specific markers on their surface. The use of such anti-cancer toxins in medicine is mainly hampered by their high non-specific toxicity, in particular, hepatotoxicity. In our work on human cell line, we have shown that the removal of the DARPin-PE40 translocation toxin domain leads to a decrease in hepatotoxicity. The same effect is also observed when inactivation of the furin cleavage site in the DARPin-PE40 molecule was done. Simultaneous removal of both the translocation domain and the furin cleavage site showed the best results. This toxin modification can be used to create more selective anti-cancer toxins.

The Application of Recombinant Phototoxins 4D5scFv-miniSOG and DARPin-miniSOG to Study the HER2 Receptor Internalization.

It was found that the fluorescent properties of the phototoxic domain of miniSOG allow to assess the ability of toxins to bind to human breast adenocarcinoma cells SK-BR-3 and study the dynamics of their internalization. We established that the main cause of the decrease of the fluorescence intensity of the recombinant proteins 4D5scFv-miniSOG and DARPin-miniSOG during their internalization in the complex with the HER2 receptor is their shielding and absorption of the fluorescence of miniSOG by the cells fluorophores.

Death Mechanism of Breast Adenocarcinoma Cells Caused by BRET-Induced Cytotoxicity of miniSOG Depends on the Intracellular Localization of the NanoLuc-miniSOG Fusion Protein.

Photodynamic therapy (PDT) is widely used in clinical practice to influence neoplasms in the presence of a photosensitizer, oxygen, and light source. The main problem of PDT of deep tumors is the problem of delivering excitation light (without lost of its intensity) inside the body. An alternative to the external light sources can be the internal light sources based on luciferase-substrate bioluminescent systems. In our work, we used the NanoLuc-furimazine system as an internal light source. This system can be successfully used to excite the protein photosensitizer miniSOG and to induce the phototoxicity of this flavoprotein in cancer cells during bioluminescent resonance energy transfer (BRET). It was shown that the mechanism of cell death caused by BRET-induced phototoxicity of mimiSOG in the presence of furimazine depends on the intracellular localization of the NanoLuc-miniSOG fusion protein: BRET-mediated activation of miniSOG in mitochondrial localization causes apoptosis, while the membrane localization of PS causes necrosis of cancer cells.

Synthesis of Magnetic Nanoparticles Stabilized by Magnetite-Binding Protein for Targeted Delivery to Cancer Cells.

A new method for obtaining biomodified magnetite nanoparticles for targeted delivery to cells was developed. The method is based on the use of the C-terminal fragment of the Mms6 protein, which is involved in the magnetite biomineralization during the synthesis of magnetosomes in magnetotactic bacteria Magnetospirillum magneticum AMB-1, and the barnase*barstar high-affinity protein pair. The Mms6 protein fragment is required for stabilizing magnetite, and the barnase*barstar pair mediates the interaction between nanoparticles and the component for modification. The efficiency of this method was confirmed in the synthesis of magnetite nanoparticles recognizing the HER2/neu tumor marker and in the selective labeling of HER2/neu with these nanoparticles on the surface of cancer cells.

Cytotoxicity of targeted HER2-specific phototoxins based on flavoprotein miniSOG is determined by the rate of their internalization.

The concept of targeted therapy implies the development of bifunctional agents complementing the therapeutic module with a targeting one. A promising target for the delivery of imaging and/or toxic modules is the HER2 (ErbB2) receptor. Earlier, we have functionally characterized the targeted photosensitizers 4D5scFv-miniSOG and DARPin-miniSOG, causing the death of HER2-overexpressing cells when irradiated with blue light. However, the cytotoxicity of targeted toxins 4D5scFv-miniSOG and DARPin-miniSOG (both having functionally active targeted and cytotoxic modules in recombinant proteins) against human breast adenocarcinoma cells differs 5 times. The study of the dynamics of internalization of 4D5scFv-miniSOG and DARPin-miniSOG proteins in the complex with HER2 in this work showed that the rate of internalization contributes most significantly to the toxicity of these photosensitizers, because it determines the duration of the presence of the phototoxin in the lipid bilayer of the cell membrane, where its damaging effect is maximum.

Flavoprotein miniSOG BRET-induced cytotoxicity depends on its intracellular localization.

It is proposed to use the bioluminescent resonance energy transfer to solve the problem of creating the internal light sources in photodynamic therapy of cancer. Energy donor in the developed system is the oxidized form of the luciferase NanoLuc substrate furimamide, and acceptor is the phototoxic fluorescent protein miniSOG. It is shown that, in the proposed system, the photoinduced cytotoxicity of flavoprotein miniSOG in vitro depends on the intracellular localization, and the cytotoxic effect is 48% for the cytoplasmic localization of the fusion protein, 65% for the mitochondrial localization, and 69% for the membrane localization. The obtained data indicate that, for maximization of the photodynamic effect in vivo, it is appropriate to use the NanoLuc-miniSOG fusion protein in the membrane localization.

Approximate analytic solution of a simple system of kinetic equations describing the enzymatic synthesis of nucleic acids.

Macroscopic kinetic models describing the process of polymerase chain reaction (PCR) are currently solved only by numerical methods, which hampers the development of effective software algorithms for processing the results of the reaction. This paper considers the application of the homotopy perturbation method for obtaining approximate analytical solution of the simplest system of enzymatic kinetic equations describing the synthesis of nucleic acid molecules during PCR. The resulting approximate analytic solution with high accuracy reproduces the results of a numerical solution of the system in a wide range of ratios of enzyme and substrate concentrations both for the case of a large excess of the substrate over the enzyme and vice versa.

[Results of the modified Appleby procedure].

AIM: To evaluate safety and efficacy of distal pancreatectomy with en bloc celiac artery resection (DP-CAR) for pancreatic malignancy. MATERIAL AND METHODS: Medical reports of 17 patients who underwent DP-CAR procedure (15 of them with pancreatic malignancy) were retrospectively analyzed. Also we studied 27 publications describing more than 2 cases of DP-CAR. RESULTS: R0- and R1-resection was performed in 14 (82%) and 3 (18%) patients respectively. Postoperative complications ware observed in 11 (65%) cases. Nine of them were successfully treated. Full pain control was achieved in all patients. There were no any ischemic complications. 16 patients received chemotherapy. 2 (11%) patients died in early postoperative period due to aortic dissection in 10 days and fungal sepsis in 44 days after surgery. Median survival was 20 months. Literature review included 27 articles describing 311 operations. Herewith postoperative complications developed in 43% of cases and 90-day postoperative mortality was 4%. Median survival ranged from 9.3 to 26 months. CONCLUSION: DP-CAR is effective and safe procedure in certain patients with locally advanced pancreatic cancer.

Mathematics analysis of polymerase chain reaction kinetic curves.

The paper reviews different approaches to the mathematical analysis of polymerase chain reaction (PCR) kinetic curves. The basic principles of PCR mathematical analysis are presented. Approximation of PCR kinetic curves and PCR efficiency curves by various functions is described. Several PCR models based on chemical kinetics equations are suggested. Decision criteria for an optimal function to describe PCR efficiency are proposed.

Development and investigation of recombinant immunotoxin protein 4D5scFv-mCherry-PE(40).

Development of agents for theranostics implies combining the targeting module, the effector module, and the detection module within the same complex or recombinant protein. We have constructed, isolated, and characterized the 4D5scFv-mCherry-PE(40) protein, which exhibits fluorescent properties and specifically binds to cancer cells expressing the HER2 receptor and reduces their viability. The ability of the obtained targeted antitumor agent 4D5scFv-mCherry-PE(40) to selectively stain the HER2-positive cells and its highly selective cytotoxicity against these cells make the obtained targeted recombinant protein 4D5scFv-mCherry-PE(40) a promising theranostic agent for the diagnostics and therapy of HER2-positive human tumors.

Alternative solution of the simplest model of enzymatic synthesis of nucleic acids by homotopy perturbation method.

Development of methods for obtaining approximate analytical solutions of nonlinear differential equations and their systems is a rapidly developing field of mathematical physics. Earlier, an approximate solution of the simplest system of kinetic enzymatic equations for calculating dynamics of complementary strands of nucleic acids was obtained. In this study, we consider an alternative approach to selecting the basic linear approximation of the used method, which makes it possible to obtain more accurate analytical solutions of the set problem.

A comprehensive study of interactions between lectins and glycoproteins for the development of effective theranostic nanoagents.

A comprehensive study of the interactions between lectins and glycoproteins possessing different glycosylation profiles in the composition of nanoparticles was carried out in order to find specifically interacting protein pairs for the creation of novel classes of multifunctional nanoagets that based on protein-assisted selfassembly. We obtained information about specific interactions of certain lectins with selected glycoproteins as well as about the ability of certain monosaccharides to competitively inhibit binding of glycoproteins with lectins. These protein-mediated interactions may be involved in the formulation of self-assembled nanoparticles for therapy and diagnostics of various diseases.

Far-red fluorescent cell line for preclinical study of HER2-targeted agents.

We have created novel HER2-overexpressing human ovarian adenocarcinoma cell line stably transfected with far-red fluorescent protein TurboFP635. Growth characteristics, adhesion capacity and morphology of the cells do not differ from that of parental cell line. The obtained cell line (SKOV-kat) was confirmed to have high level of expression of the tumor marker HER2 comparable to that of initial cell line SKOV-3. The SKOV-kat cell line is designed for further establishment of experimental fluorescent models of HER2-overexpressing human ovarian cancer that make it possible to optimize and reduce the cost of preclinical study of agents for treatment of this disease.

Pancreas-preserving approach to "paraduodenal pancreatitis" treatment: why, when, and how? Experience of treatment of 62 patients with duodenal dystrophy.

BACKGROUND: The term "paraduodenal pancreatitis" (PP) was proposed as a synonym for duodenal dystrophy (DD) and groove pancreatitis, but it is still unclear what organ PP originates from and how to treat it properly. OBJECTIVE: To assess the results of different types of treatment for PP. METHOD: Prospective analysis of 62 cases of PP (2004-2013) with histopathology of 40 specimens was performed; clinical presentation was assessed and the results of treatment were recorded. RESULTS: Preoperative diagnosis was correct in all the cases except one (1.9%). Patients presented with abdominal pain (100%), weight loss (76%), vomiting (30%), and jaundice (18%). CT, MRI, and endoUS were the most useful diagnostic modalities. Ten patients were treated conservatively, 24 underwent pancreaticoduodenectomies (PD), pancreatico- and cystoenterostomies (8), Nakao procedures (5), duodenum-preserving pancreatic head resections (5), and 10 pancreas-preserving duodenal resections (PPDR) without mortality. Full pain control was achieved after PPRDs in 83%, after PDs in 85%, and after PPPH resections and draining procedures in 18% of cases. Diabetes mellitus developed thrice after PD. CONCLUSIONS: PD is the main surgical option for PP treatment at present; early diagnosis makes PPDR the treatment of choice for PP; efficacy of PPDR for DD treatment provides proof that so-called PP is an entity of duodenal, but not "paraduodenal," origin.