CDK9 inhibition as an effective therapy for small cell lung cancer.

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.

Li4GeO4-Li2CaGeО4 phase equilibria and Li2+xCa1-xGeO4 solid solutions.

Detailed studies of the Li4GeО4-Li2CaGeО4 system by solid-phase syntheses of various compositions from pure Li4GeО4 to pure Li2CaGeО4 in the temperature range from 25 to 1125 °C is investigated for a first time. Solid state synthesis powders are characterized by X-ray and DSC/TG methods. Concentration and temperature two-phase regions of Li4GeО4 and Li2CaGeО4 as well as two-phase regions of Li2CaGeО4 and Li2+2xCa1-xGeO4 are established. Region of pure Li2+2xCa1-xGeO4 solid solution are detected too and it structure is investigated. Being structural analog to Li2+2xZn1-xGeO4 and Li2+2xMg1-xGeO4, Li2+2xCa1-xGeO4 has own specific local environment of the metal ions. The obtained results are compared with those for Li4GeО4-Li2ZnGeО4 system and for Li2+2xZn1-xGeO4 solid solution. The differences of the phase diagrams and structural features of the solid solutions are discussed.

Tennis elbow, study protocol for a randomized clinical trial: needling with and without platelet-rich plasma after failure of up-to-date rehabilitation.

BACKGROUND: The conservative management of lateral epicondylitis is known to be a difficult-to-treat annoying condition. A treatment with platelet-rich plasma (PRP) is often performed, but its efficacy remains controversial. METHODS: This study is a single-center, randomized double-blind controlled trial, preceded by a case series. All the 232 planned patients of the case series will undergo an up-to-date comprehensive rehabilitation program, including focused extracorporeal shock waves therapy. This rehabilitation program is expected to have a maximum success rate 75%. It is therefore aimed to allocate a minimum of 58 patients with rehabilitation failure into the 1:1 randomized trial. Stratification is planned on age and lesion pattern. The masking will be quadruple (Participant, Care Provider, Investigator & Outcome Assessor). The patients will undergo an ultrasound (US)-guided needling combined with either PRP (intervention group) or saline (control group). The primary endpoint will be the pain improvement from baseline (month 0) at 3 months on a 0-10 visual analog scale (VAS) during a maximal strength isometric contraction of the extensor carpialis brevis muscle. The main secondary endpoints will include the rehabilitation success rate and improvements from baseline at 3, 6, and 12 months of the following outcomes: (i) Single Assessment Numeric Evaluation (SANE) score, (ii) Patient-Rated Tennis Elbow Evaluation (PRTEE) score, (iii) maximal grip strength on Jamar test, and (iv) the ultrasonographic evaluation of the US of the epicondylar tendons. DISCUSSION: The study results will provide insight into the effect of PRP as adjuvant therapy to tendon fenestration, and may contribute to identify the best preceding and concomitant rehabilitation protocol. TRIAL REGISTRATION: ClinicalTrials.gov NCT03987256. Registered on 20 August 2019.

Spectroscopic investigations of nanosized Cr3+ doped Sc2-x Inx (WO4 )3 : A new promising laser material.

Chromium(III) doped nanosized Sc2-x Inx (WO4 )3 , (x = 0-2) solid solutions were prepared by the co-precipitation/calcination method. The obtained powders were characterized using X-ray diffraction (XRD), electron paramagnetic resonance (EPR), infrared (IR), absorption and luminescence spectra. X-ray analysis showed that the compounds are pure solid solutions with orthorhombic symmetry at x values 0 and 0.5 and with monoclinic symmetry for x values 1.0, 1.5 and 2.0. The calculated crystallite size ranged from about 20 to 110 nm, except for Sc2 (WO4 )3 characterized by considerably larger sizes. IR spectra of the solid solutions contain the characteristic vibrations of the WO4 and MeO6 , (Me = Sc, In) polyhedra, building the Sc2 (WO4 )3 and In2 (WO4 )3 structures. EPR analysis proved the presence of isolated Cr3+ ions in the crystal field with rhombic symmetry. The presence of Cr3+ in sites with weak and strong crystal field was revealed by absorption and luminescence spectra. This study demonstrates the effect of hosts crystal symmetry, particles size and doping concentration on the luminescence properties.

ONE-STAGE (PRIMARY) RECONSTRUCTIONS OF RESECTION MANDIBULAR DEFECTS BY MEANS OF AUTOGENE VASCULARISED ILIAC AND FIBULAR TRANSPLANT.

UNLABELLED: Mandibular resections are most often performed in cases of tumour ablations. Contemporary oral and maxillofacial surgery acknowledges primary one-stage reconstructions of defects through microvscularised transplants. They have intact circulation due to the primarily performed vascular anastomoses. For recovery of the shape and the function of the mandible most frequently used transplants are derived from the iliac crest and fibula. Goal and objectives. We share our experience in the one-stage recovery of mandibular defects simultaneously with the resection, by means of autogene vascularised iliac and fibular transplants. Material and method. 8 patients aged from 24 to 61 (female - 1, male - 7) with tumours engaging the mandible (5 - benign and 2 - malignant) were treated surgically and followed up. We carried those out using extraoral approach in 7 cases, and intraoral aproach - in 1. The resulting post resection mandibular defects in 3 of the patients were reconstructed by means of one-stage autogene bone vascularised iliac transplants. In 5 patients the defects were recovered primarily through vascularised fibular autotransplants. The surgical techniques and protocols, to assess the outcome and characterize of the methods are presented. RESULTS: We tracked down the postoperative results of the mandibular reconstructions for a period of 1 to 3 years. Support for the lips and tongue was achieved providing for satisfactory speech and feeding. Anatomical remodeling was observed. The conditions for the production of dental implants were improved. In the case, when we used intraoral approach the facial aesthetics was fully restored, as for the rest it was satisfactory. CONCLUSIONS: Vascularised autogene iliac and fibular bone transplants are extremely appropriate for reconstructions of significant and complicated mandibular and other defects in the maxillofacial area. Their survival is independent from the recipient area, and secured through the vessel anastomoses. With sound surgical technique, success rate of the method is to a large extent guaranteed.

Renal histopathology and clinical course in patients with Wegener's granulomatosis--single centre experience from the Republic of Macedonia.

The aim of this study was to evaluate the clinical course of patients with Wegener's granulomatosis (WG) with renal involvement, to examine histopatological form seen in renal biopsies and present follow-up of the patients. A retrospective analysis was carried out of 18 patients presenting with WG and active renal disease at the University Nephrology Department, Ss. Cyril and Methodius University, Skopje, R. Macedonia. All patients were ANCA positive and had a percutaneous renal biopsy taken on their admission. 12 patients were male, 6 female, aged 48.61±13.77 (M±SD). All had extrarenal symptoms prior to admission. Oligoanuria was present in 7/18 (38.9%) of the patients, serum urea levels of the whole group were 40.67±18.13 mmol/l (M±SD) and for serum creatinine 691.06±384.93 µmol/l (M±SD). Necrotizing glomerulonephritis with crescents was present in 11/18 (61.11%) of the patients, the others presented diffuse proliferative extracapillary glomerulonephritis. All patients were treated with steroids and cyclophosphamide, and plasmapheresis was performed in 7/18 (38.9%) of the patients. Probability rate for surviving after one month was 0.6111 and after three months 0.3889 (Kaplan-Meier). The current treatment of WG in our study did not prevent serious complications and development of ESRD in a large number of our patients. This systemic disorder is still a serious problem and early diagnosis and alternative strategies for the management of the disease will be an important objective for further studies.

Radiological and "imaging" methods in TNM classification of non-small-cell lung cancer.

Lung cancer is the most common worldwide malignant disease according to its incidence and mortality. The aim of our study was to evaluate the diagnostic value of the radiological and imaging methods, according to the TNM classification, compared to postoperative histological diagnosis. Thirty-seven patients with pulmonary carcinoma were studied prospectively using native chest radiography (PA and LL view), computed tomography (CT) and magnetic resonance imaging (MRI) during ten days before thoracotomy. Radiological and imaging findings were reviewed separately and results were compared with surgical and pathohistological findings on the basis of the TNM classification. All patients underwent chest x-rays, CT was performed in 36 patients and MRI in 12 of them. Imaging methods (CT and MRI) showed more accuracy in sensitivity and specificity compared with the native chest radiography in a great percentage. Generally no statistically significant differences were found between the two imaging methods for the evaluation of tumour extent (T) or lymph node metastases (N). MRI was slightly superior to CT in determination of the chest wall extent of the tumour. In conclusion CT remains the imaging modality of choice both for assessing patients with abnormal chest radiographs suspected of having lung cancer, and in staging patients with histologically proven pulmonary carcinoma.

Survival of patients on maintenance haemodialysis over a twenty-year period.

Patient survival is a key index of the overall adequacy of treatment in most chronic diseases. Analyses of survival of patients undergoing haemodialysis is very important, as it may offer clues and ideas for prolonging survival of patients with end-stage renal disease (ESRD). The aims of this study were to describe the characteristics of the patients on maintenance haemodialysis therapy over a period of 20 years, to determine the survival rate of these patients according to ages at the onset of haemodialysis, the primary renal diseases, and the cause of death, and to determine the survival rate at five, ten, fifteen and twenty years of haemodialysis treatment at our centre. The charts of 518 unselected patients, 282 male and 236 female, treated with maintenance haemodialysis therapy in a period of 20 years (1985-2005) were reviewed. At the time of evaluation, 164 patients were currently being treated, and 354 patients overall had been diseased. Statistical analysis was performed to evaluate the relationship between survival and patient characteristics such as age, gender, primary renal disease, and age at dialysis onset. Actual survival rates were determined by the Kaplan-Meier method. The survival rate of our patients treated with maintenance haemodialysis was 60% at 5 years, 37% at 10 years, 25% at 15 years and 9% at 20 years. Female patient survival was superior to male. Patients aged under 40 at the start of dialysis had a better survival probability compared to older patients. Patients with diabetes mellitus and nephroangiosclerosis, had a lower survival rate compared to patients with glomerulonephritis and with adult dominant polycystic kidney disease. Cardiac death was the most common cause of death in patients involved in the study. About 52% of the patients died from cardiovascular disease. Death is the most severe consequence of inadequate dialysis and can be used as an index of the adequacy of the dialysis therapy. Treatment factors that may improve outcomes include an early start of dialysis therapy, a high dose of dialysis (Kt/V over 1.2), correction of anemia, adequate protein and caloric intake, control of calcium and phosphate metabolism, and the use of biocompatible dialyzers.

IgA nephropathy: 23 years of follow-up.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis. Some patients reach end-stage renal failure (ESRF), others experience an indolent course. We aimed the study to examine the association of risk factors with the progression to renal failure. Eighty patients diagnosed with IgAN by renal biopsy (RB) were studied. Baseline clinical and demographic data were reviewed. Severity of histological involvement was scored as H. S. Lee's grading system. The mean age of patients at biopsy was 36.65 +/- 8.83 years with predominance of men (male : female, 58 : 22). Patients were followed-up from 6 months to 23 years (276 months). An end-point was defined as the date when patient underwent their first haemodialysis or their last visit of follow-up. The differences in means between groups were compared by independent samples t-tests or one-way analysis of variance (ANOVA). Kaplan-Meier survival curves and Cox regression models were used to analyze the time course from renal biopsy to end points. The largest subclasses were grade I and II, with 31 patient each. Subclass III was observed in 12 patents. Subclass IV and V were found in 3 patients each. During the follow-up period, all patients with grade IV and V (after 6-48 months), five patients grade I (after 60-144 months), four patients grade II (after 48-84 months), and 7 patients from grade III (after 24-108 months) entered ESRD. Mean prioteinuria was 1.68 +/- 0.99 g/day. Macrohematuria had 32; microhematuria had 48 pts. The mean serum creatinine was 148.02 +/- 68.76 micromol/l. By multivariate analysis using the Cox regression model, grades, renal insufficiency and significant proteinuria were independent prognostic factors for progressive renal disease. At the end of follow-up, grades were significantly related to serum creatinine, proteinuria, hypertension and progressive renal disease. Renal biopsy in IgAN may be the most powerful predictor for renal outcome.

Implementing the water framework directive in Bulgaria: Integrated river basin management on the Black Sea coast.

EC member states and candidate countries are in the process of implementing the requirements of the EC Water Framework Directive 2000/60, which came into force on 22 December 2000. At the core of the Directive is an integrated approach for sustainable water management in river basin districts. The overall objective is to reach good water status for all waters by the year 2015. The challenges for countries implementing the Directive are substantial not least for the River Basin Management Authorities who will be the implementing unit at the regional level. The Black Sea River Basin Directorate in Varna is one of four Directorates established in Bulgaria in 2002 in accordance with the Bulgarian Water Act and is the regional operational unit under the Ministry of Environment and Water for the Black Sea Basin catchment area. The catchment area covers 20% of Bulgaria and 100% of the Bulgarian Black Sea coast. Current implementation activities in the Black Sea Basin Directorate and also at the national level are supported by the Danish EPA through its DANCEE programme in collaboration with the Ministry of Environment and Water. This paper highlights the main activities and outputs of the technical and institutional undertakings in the Black Sea Basin Directorate focusing on the preparation of the River Basin Overview by Dec. 2004.

Continuous-wave lasing of a stoichiometric Yb laser material: KYb(WO4)2.

For the first time to the authors' knowledge, continuous-wave laser emission of the stoichiometric crystal KYb(WO4)2 was achieved at 1068 nm. The 125-microm-thin sample was directly water cooled and pumped at 1025 nm by a Ti:sapphire laser. The maximum output power at room temperature was 20 mW.

Survival of patients on chronic hemodialysis: single center experience.

Patient survival from our hemodialysis (HD) center over the past 11 years was analyzed. Four hundred four patients, 212 female and 192 male, were treated by chronic intermittent HD. Patients were offered standard acetate-cellulosic membranes of 1.0-1.3 m2. During this period 181 patients died. One hundred three patients were transferred to other HD centers, and some were transplanted. One hundred twenty patients are still on HD treatment. The 5 year survival rate of patients treated in our center was 58%. Women lived longer than men, and age correlated significantly with survival rate. Patients with chronic glomerulonephritis and adult polycystic kidney disease had the best survival rates while diabetic patients and those with post hypertensive nephropathy had the poorest survival rates. Forty-four percent of patients had a cardiac related cause of death, cerebrovascular accident was the cause in 15%, and 11% died due to septic condition (infection) while 8% died due to liver disease.

Organization and work of the War Hospital in Sturba near the town of Livno, Bosnia and Herzegovina.

The work of the Croatian Defense Council (armed forces of the Croatian citizens of Bosnia and Herzegovina) War Hospital at Sturba, outskirts of the town of Livno, is described. The hospital was established in the beginning of April and worked until September 1992. It provided services for the battlefield of approximately 100 km of a very difficult mountainous terrain. The hospital was situated in a concrete dugout taken from the Yugoslav Federal Army. It was well equipped and supplied exclusively by numerous donations. Medical personnel were recruited partly from local medical professionals and partly from volunteers from Croatia. During the 5-month period, 597 patients (571 soldiers and 26 civilians) were admitted. A total of 314 operations, 141 in general and 173 in regional anesthesia, were performed. None of the patients died in the hospital. There was not a single epidemic either among soldiers or civilians in the area.

NATO war medicine doctrine revisited in Bosnia and Herzegovina.

NATO war medical doctrine was applied in the war in Croatia, Bosnia and Herzegovina. However, due to rather specific martial and organizational circumstances, the doctrine had to be modified. sometimes substantially. A medical team from the war hospital in Livno, Bosnia and Herzegovina describes their work with respect to the four-echelon NATO doctrine. The team covered a relatively large and active battlefield, and treated 597 patients with 314 major surgical interventions. Due to the lack of surgeons and medical personnel in general, the second echelon concentrated on fast transportation, and the third echelon fulfilled the function of the fourth echelon, completing the surgical treatment except for 12 patients with head and spine injuries.

The therapeutic efficacy of VBCMP-M2 protocol in multiple myeloma.

Within a period from March 1983 to November 1988, 93 newly diagnosed patients with multiple myeloma, 47 men and 46 women aged from 41 to 80 years were treated with protocol VBCMP-M2. A response was achieved in 30 (60%) patients in stage II and 22 (51%) in stage III, the overall response rate being 56%. 41% of all patients entered plateau phase, more frequently in stage II (46%) than in stage III (37%) patients. The median survival of all patients was 35 months. Comparing these groups of patients with other series from the literature, we were not able to demonstrate any advantage of this multidrug combination over other combinations or even melphalan and prednisone alone.

[Antinuclear antibodies detection in both HEp-2 cells and tissue section of the rat liver using indirect imunofluorescence]. / Okkrivanje antinukleusnih antitela indirektnom imunofluorescentom metodom na humanim epitelijalnim celijama-dva i tkivnim iseccima jetre pacova.

Having in mind the importance of indirect immunofluorescence in antinuclear antibodies detection, the study was aimed to compare characteristics of fluorescent visualization and specificity of HEp-2 cells with tissue cryosections of the rat liver. The study included 76 serum samples obtained from patients with systemic connective tissue diseases. Out of that number, fluorescence findings on HEp-2 cells and rat liver tissue were positive in 74 and 54 patients, respectively. At the same time, only foyr basic types of fluorescence were manifest in tissue samples, while HEp-2 cells revealed 3 mixed types, and within the patchy type, several subgroups were evidenced. Out of the 20 serum samples which enabled positive results only with HEp-2 cells, they all belonged to the group of patchy fluorescence. In addition to the better fluorescence visualization, owing to its more complexs antigenic structure. HEp-2 cells revealed significantly higher specificity when compared to the rat liver tissue thus enabling definitive identification of sertain specific autoantibodies, or they were used as screening methods for its further detection.

Epidemiology of hepatitis D virus (delta) infection in Yugoslavia.

In 614 HBsAg-positive Yugoslavian patients, radioimmunoassay testing for anti-delta showed the presence of this antibody in serum in 11.2%. Of the patients, 213 belonged to a risk group (i.v. drug users, hemophiliacs, hemodialysed patients and patients with posttransfusion hepatitis); a significant number of these patients (63; 29.6%) were found to have anti-delta. A second group was composed of 401 HBsAg-positive patients from the general population (patients with acute hepatitis B, with fulminant hepatitis B and patients with chronic HBV infection); delta infection was found only in six (1.5%). Immunohistochemical methods failed to demonstrate the delta antigen in the livers of 73 patients with chronic HBV infection. Testing the liver of 36 patients with fulminant hepatitis B for delta antigen demonstrated this reactivity in only one (2.8%) liver sample. Delta antigen was also found in the liver of a female patient who underwent biopsy in 1972. The results of this study suggest the HDV is not endemic in Yugoslavia; however, it is frequently found in patients at risk of blood exposure, primarily i.v. drug users.

[A retrospective survey study of diagnosis and surgical treatment in peptic ulcer]. / Obzorno retrospektivno prouchvane vurkhu diagnozata i khirurgichnoto lechenie na iazvenata bolest.

A total of 239 patients of which 183 operated over the period 1987 through 1992 are reviewed. Cases with duodenal location of the lesion predominate (84 per cent), next ranking gastric ulcers (14 per cent), and type II according to Johnson (2 per cent). Among the patients operated on resection methods, type Billroth II, with antecolic gastroenteroanastomosis and Braun's anastomosis, accounting for 84.1 per cent of the total of planned operations, are mainly used. Retrocolic gastroenteroanastomosis type Hoffmeister-Finsterer is performed in five, and Billroth I-in one patient. Three patients presenting gastric ulcer, free of malignization signs, are subjected to pylorus-preserving resection according to MacKee. Resection methods as a definitive therapeutic approach to ulcers, at that according to Billroth II, are predominant owing to the fact that most patients operated on present ulcers penetrating the pancreas, involving ligamentum hepatoduodenale and the descending portion of the duodenum, and pyloric stenosis, making impossible the restoration of passage by Billroth I or other operations. A lasting good result is attained in 92 per cent of cases, minor complaints are recorded in 6 per cent, and substantial complaints-in 2 per cent. The study results lead to the inference that standard resections with anterior gastroenteroanastomosis in complicated ulcers, ruling out other alternatives, yield a permanent therapeutic effect. The approach to individual patients should be by no means unified, and the most expedient operative procedure should be used. Owing to delayed operative treatment and numerous complications, the classical resection methods prove to be the method of choice in the surgical management of ulcers.

[The zinc concentration of the maternal serum and the amniotic fluid in pregnancies with fetal neural defects in the second trimester]. / Kontsentratsiia na tsink v maichin serum i okoloplodna technost pri bremennosti s nevralni defekti na ploda vuv vtori trimestur.

The object of the investigation are 120 pregnancies in the second trimester, 38 of which are with prenatally proved neural tube defects of the fetus (anencephaly, spina bifida, hydrocephaly) and 82 with morphologically normal developed fetuses. There have been examined vein blood of the pregnant woman and amniotic fluid after transabdominal amniocentesis as there has been determined zinc status in both of the biological fluids. The average serum's zinc concentration at malformed pregnancies is without statistically considerable difference in comparison with this of the group--healthy pregnancies. Amendable zinc's concentration at cases with neural tube defects are statistical considerably higher than these in the control group. A survey of literary data, devoted to the theory of zinc deficiency as a teratogen in the human pregnancy, has been made during the last years. Up to the author's opinion, there have been represented the most acceptable explanations about the abnormal values of the zinc amenable concentration at neural tube defects in the fetus.