Integrated structure-based protein interface prediction.

BACKGROUND: Identifying protein interfaces can inform how proteins interact with their binding partners, uncover the regulatory mechanisms that control biological functions and guide the development of novel therapeutic agents. A variety of computational approaches have been developed for predicting a protein's interfacial residues from its known sequence and structure. Methods using the known three-dimensional structures of proteins can be template-based or template-free. Template-based methods have limited success in predicting interfaces when homologues with known complex structures are not available to use as templates. The prediction performance of template-free methods that only rely only upon proteins' intrinsic properties is limited by the amount of biologically relevant features that can be included in an interface prediction model. RESULTS: We describe the development of an integrated method for protein interface prediction (ISPIP) to explore the hypothesis that the efficacy of a computational prediction method of protein binding sites can be enhanced by using a combination of methods that rely on orthogonal structure-based properties of a query protein, combining and balancing both template-free and template-based features. ISPIP is a method that integrates these approaches through simple linear or logistic regression models and more complex decision tree models. On a diverse test set of 156 query proteins, ISPIP outperforms each of its individual classifiers in identifying protein binding interfaces. CONCLUSIONS: The integrated method captures the best performance of individual classifiers and delivers an improved interface prediction. The method is robust and performs well even when one of the individual classifiers performs poorly on a particular query protein. This work demonstrates that integrating orthogonal methods that depend on different structural properties of proteins performs better at interface prediction than any individual classifier alone.

A systematic review of craniospinal irradiation for leptomeningeal disease: past, present, and future

Purpose Leptomeningeal disease (LMD) is a rare but deadly complication of cancer in which the disease spreads to the cerebrospinal fluid and seeds the meninges of the central nervous system (CNS). Craniospinal irradiation (CSI) involves treatment of the entire CNS subarachnoid space and is occasionally used as a last-resort palliative therapy for LMD. Methods This review examined literature describing the role of CSI for LMD from solid and hematologic malignancies in adults. A search for studies published until September 1, 2020 was conducted using PubMed database. Results A total of 262 unique articles were identified. Thirteen studies were included for analysis in which a total of 275 patients were treated with CSI for LMD. Median age at time of irradiation was 43 years, and most patients had KPS score of 70 and higher. The most common cancers resulting in LMD were acute lymphocytic leukemia, breast cancer, and acute myelogenous leukemia. Median CSI dose was 30 Gy and 18% of patients were treated with proton radiation. 52% of patients had stable-to-improved neurologic symptoms. Median overall survival for the entire cohort was 5.3 months. Patients treated with marrow-sparing proton radiation had median OS of 8 months. The most common treatment toxicities were hematologic and gastrointestinal events. Conclusions Despite advances in systemic and radiation therapies, LMD remains a devastating end-stage complication of some malignancies. Treatment-related toxicities can be a significant barrier to CSI delivery. In select patients with LMD, marrow-sparing proton CSI may provide safer palliation of symptoms and prolong survival (AU)

A systematic review of craniospinal irradiation for leptomeningeal disease: past, present, and future.

PURPOSE: Leptomeningeal disease (LMD) is a rare but deadly complication of cancer in which the disease spreads to the cerebrospinal fluid and seeds the meninges of the central nervous system (CNS). Craniospinal irradiation (CSI) involves treatment of the entire CNS subarachnoid space and is occasionally used as a last-resort palliative therapy for LMD. METHODS: This review examined literature describing the role of CSI for LMD from solid and hematologic malignancies in adults. A search for studies published until September 1, 2020 was conducted using PubMed database. RESULTS: A total of 262 unique articles were identified. Thirteen studies were included for analysis in which a total of 275 patients were treated with CSI for LMD. Median age at time of irradiation was 43 years, and most patients had KPS score of 70 and higher. The most common cancers resulting in LMD were acute lymphocytic leukemia, breast cancer, and acute myelogenous leukemia. Median CSI dose was 30 Gy and 18% of patients were treated with proton radiation. 52% of patients had stable-to-improved neurologic symptoms. Median overall survival for the entire cohort was 5.3 months. Patients treated with marrow-sparing proton radiation had median OS of 8 months. The most common treatment toxicities were hematologic and gastrointestinal events. CONCLUSIONS: Despite advances in systemic and radiation therapies, LMD remains a devastating end-stage complication of some malignancies. Treatment-related toxicities can be a significant barrier to CSI delivery. In select patients with LMD, marrow-sparing proton CSI may provide safer palliation of symptoms and prolong survival.

Diffraction based Hanbury Brown and Twiss interferometry at a hard x-ray free-electron laser.

X-ray free-electron lasers (XFELs) provide extremely bright and highly spatially coherent x-ray radiation with femtosecond pulse duration. Currently, they are widely used in biology and material science. Knowledge of the XFEL statistical properties during an experiment may be vitally important for the accurate interpretation of the results. Here, for the first time, we demonstrate Hanbury Brown and Twiss (HBT) interferometry performed in diffraction mode at an XFEL source. It allowed us to determine the XFEL statistical properties directly from the Bragg peaks originating from colloidal crystals. This approach is different from the traditional one when HBT interferometry is performed in the direct beam without a sample. Our analysis has demonstrated nearly full (80%) global spatial coherence of the XFEL pulses and an average pulse duration on the order of ten femtoseconds for the monochromatized beam, which is significantly shorter than expected from the electron bunch measurements.

A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer.

BACKGROUND: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. PATIENTS AND METHODS: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. RESULTS: Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. CONCLUSIONS: These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT01285557.

[The assessment of surgical treatment of patients with malignant pleural effusion].

An analysis of results of 498 patients with malignant pleural effusion was made. All patients were divided into three groups depending on methods of treatment: in the first group of patients the puncture of pleural cavity and the evacuation of liquid were made against the background of complex treatment; in the second group of patients the thoracocentesis and suspension induction were performed; in the third group the video thoracoscopy was carried out. In an assessment of each method of treatment, the researchers came to the conclusion that in case when the patient had the sufficient functional capabilities, the doctors should give preference to the thoracoscopy operations and in case of severe somatic status the doctors should give preference to the drainage of pleural cavity with release from exudates and with subsequent introduction of talc as the most effective sclerosing agent.

[Use of thrombin generation assay for the evaluation of coagulation and anticoagulant activity of hemostasis system in patients with abdominal sepsis].

Generally recognized factor, which complicates the course of sepsis, is the development of hypercoagulation syndrome. The increase of thrombin coagulation indicates on the elevation of risk of thrombus formation in microcirculation vessels, which could cause the formation of multiple organ failure. The thrombin generation assay is a new method of the evaluation of homeostasis system status. The test reflects the fermentation activity of thrombin and shows the functional condition, which arises in the interaction of procoagulant and anticoagulant. The diagnosis of generalized peritonitis had 30 patients (18 men and 12 women, aged 61+/-18,3 years) and they were included in the research. It was shown, that the use of thrombin generation assay in patients with the abdominal sepsis could give the well-timed analysis of hypercoagulation changes and the assessment of protein C system investment in the thrombin generation.

[Assessment of endogenous thrombin potential and influence on it of different regimens of heparin therapy in patients with abdominal sepsis].

Abdominal sepsis (AS) is a systemic inflammatory reaction of organism in response to the development of infectious process in organs of the abdominal cavity. The course of AS is complicated by hypercoagulation syndrome which facilitates progression of endogenous intoxication. The investigation included 26 patients (14 men and 12 women, mean age 65.5 +/- 16.4 years) with AS. The test of thrombin generation (TTG) used in patients with AS allows assessment of changes in the hemostasis system and control of the heparin dose. It was established that TTG revealed elevated endogenous thrombin potential of blood practically in all patients with AS. In the patients given 25 000 IU of heparin the TTG indices showed a reliably decreased endogenous thrombin potential and peak thrombin concentration as compared with a group of patients given 10 000 IU of heparin.

[Prophylactics and treatment of peritoneal commissures].

The means for using prophylactic measures for prevention of the development of the adhesion process in the abdominal cavity are divided by the authors into two groups: for primary and secondary prophylactics. The mechanism of action of means for primary prophylactics is directed to restoration of the peritoneum mesothelium and its function; secondary prophylactics--to prevention of adhesions of scarry regenerated leaves of the parietal and visceral peritoneum. The findings are analyzed. The authors give recommendations for using means against adhesions. The necessity to choose the means for prophylactics depending on the state of the abdominal cavity is grounded (first operation or reoperation, planned or emergency operation). On the basis of the personal experience the authors recommend measures of the primary and secondary prophylactics of the adhesion process.

[Treatment of malignant etiology pleurisies using videothoracoscopy].

On the basis of an analysis of results of treatment of 123 patients by different methods of pleurodesis the authors have shown advantages of the method of videothoracoscopy.

[Possibilities of palliative operations in patients with intrapulmonary metastases of renal cancer].

Results of treatment of 51 patients with intrapulmonary metastases of renal cancer were analyzed. Surgical interventions in volume of complete cytoreduction were made in 31 of them. All the patients were followed-up after operations at the period from 3 through 68 months. A multi-factor analysis has shown that surgical metastasectomy gives reliably better results of treatment of patients with disseminated renal cancer. Regressive analysis in the group of operated patients has shown that involvement of the lymph nodes of the bronchopulmonary group and mediastinum gave reliably worse results of treatment of this group of patients.

[Cytoreductive operations in complex treatment of patients with intrapulmonary metastases of colorectal carcinoma].

An analysis of results of treatment of 112 patients with metastases of intrapulmonary colorectal carcinoma (CRC) for the period from 1990 to 2006 has shown that cytoreductive opera tions for excision of the metastases are an effective method of treatment of this category of patients which allows a two times increased survival median as compared with analogous index in the group of patients exposed to palliative chemotherapy. Palliative chemotherapy fails to have statistically significant influence to survival of patients who have ablated intrapulmonary CRC metastases in the volume of complete cytoreduction.

[Surgical prophylactics of bronchopleural fistulas after pneumonectomy].

The authors made an analysis of the results of treatment of 924 patients with non-small cell lung cancer, operated in the volume of pneumonectomy during 1990-2007 years and developed a method of complete suturing the mediastinum wound in order to isolate the bronchus stump from the free pleural cavity and prevention of the development of a bronchopleural fistula.

[Role of biological tumor markers CEA, Cyfra-21, NSE, TU M2-PK in diagnosis and treatment of lung cancer].

The authors investigated the dependence of increasing serum oncomarkers CEA, Cyfra-21, NSE, TU M2-PK on survival in 739 patients with nonsmall cell lung cancer. The tests for the determination of the content of CEA, Cyfra-21, NSE in blood serum have low sensitivity and are of little use for the diagnosis of lung cancer. The tests because of their simplicity and low cost can be used for the detection of groups of patients with preliminarily diagnosed nonsmall cell lung cancer needing additional methods of examination for more exact staging of the disease and exclusion of remote metastases and more active using adjuvant method of treatment. The use of tumor pyruvate kinase can be perspective for clinical oncopulmonology. However, due to its low specificity, further experiences are required for using this oncomarker in the group of patients with nonsmall cell lung cancer.

[State of cardiac activity in patients with varicose disease of the lower extremity veins].

The intracardiac characteristics were studied in 100 patients prior to a removal of varicose veins by surgical or screrotherapeutic methods using US methods. An analysis of these characteristics has shown that investigation of the diastolic function of the heart ventricles is the most demonstrative one. The function of one or two ventricles was shown to worsen with age having negative influence on the venous system of lower extremities which can cause the appearance of varicose veins or their progression thus increasing the stage of chronic venous insufficiency, the appearance of recurrent varicosity after its removal.