Understanding the Effect of Prescription Isodose in Single-Fraction Stereotactic Radiosurgery on Plan Quality and Clinical Outcomes for Solid Brain Metastases.

BACKGROUND AND OBJECTIVES: There is wide variation in treatment planning strategy for central nervous system (CNS) stereotactic radiosurgery. We sought to understand what relationships exist between intratumor maximum dose and local control (LC) or CNS toxicity, and dosimetric effects of constraining hotspots on plan quality of multiple metastases volumetric modulated arc therapy radiosurgery plans. METHODS: We captured brain metastases from 2015 to 2017 treated with single-isocenter volumetric modulated arc therapy radiosurgery. Included tumors received single-fraction stereotactic radiosurgery, had no previous surgery or radiation, and available follow-up imaging. Our criterion for local failure was 25% increase in tumor diameter on follow-up MRI or pathologic confirmation of tumor recurrence. We defined significant CNS toxicity as Radiation Therapy Oncology Group irreversible Grade 3 or higher. We performed univariate and multivariate analyses evaluating factors affecting LC. We examined 10 stereotactic radiosurgery plans with prescriptions of 18 Gy to all targets originally planned without constraints on the maximum dose within the tumor. We replanned each with a constraint of Dmax 120%. We compared V50%, mean brain dose, and Dmax between plans. RESULTS: Five hundred and thirty tumors in 116 patients were available for analysis. Median prescription dose was 18 Gy, and median prescription isodose line (IDL) was 73%. Kaplan-Meier estimate of 12-month LC only tumor volume (HR 1.43 [1.22-1.68] P < .001) was predictive of local failure on univariate analysis; prescription IDL and histology were not. In multivariate analysis, tumor volume impacted local failure (HR 1.43 [1.22-1.69] P < .001) but prescription IDL did not (HR 0.95 [0.86-1.05] P = .288). Only a single grade 3 and 2 grade 4 toxicities were observed; tumor volume was predictive of CNS toxicity (HR 1.58 [1.25-2.00]; P < .001), whereas prescription IDL was not (HR 1.01 [0.87-1.17] P = .940). CONCLUSION: The prescription isodose line had no impact on local tumor control or CNS toxicity. Penalizing radiosurgery hotspots resulted in worse radiosurgery plans with poorer gradient. Limiting maximum dose in gross tumor causes increased collateral exposure to surrounding tissue and should be avoided.

Prevalence of metabolic acidosis in ileal diversions more than one year after radical cystectomy and associated secondary metabolic effects.

INTRODUCTION AND OBJECTIVE: Metabolic acidosis (MA) is a well-known complication in patients with ileal urinary diversions. It is common in the early postoperative stages and decreases over time. Our objective is to investigate the prevalence of MA after more than one year of follow-up, identify the associated risk factors, and analyze its secondary metabolic consequences. MATERIALS AND METHODS: We conducted an observational study between January 2018 and September 2022 following the STROBE guidelines. MA was defined as a serum bicarbonate level ​​<22mEq/L. Finally, we analyzed 133 patients with a mean follow-up of 55.24 ± 42.36 months. RESULTS: MA was observed in 16 (12%) patients. Patients with and without MA were comparable in age, sex, and follow-up time. The group with MA presented a higher rate of anemia (68,75% vs 19,65%, p < 0.001) and renal failure (100% vs 45,29%, p < 0.001), statistically significant higher levels of serum creatinine, chloride, potassium, parathyroid hormone, and phosphorus but lower serum values ​​of hemoglobin, renal glomerular filtration rate, total cholesterol, vitamin D, calcium, and albumin (all p < 0.05). Renal glomerular filtration rate was the only independent risk factor related to the development of MA (OR 0.914; 95% CI 0.878-0.95; p < 0.0001), proving a close correlation with venous bicarbonate values ​​(r = 0.387, p < 0.001). CONCLUSIONS: MA is a little prevalent disorder in ileal urinary diversions more than one year after radical cystectomy is performed but it has secondary consequences on hematologic, renal, protein, lipid, and bone metabolism. We recommend to a close follow-up in patients with renal failure for early diagnosis and treatment.

External multicentre validation of pseudomyxoma peritonei PSOGI-Ki67 classification.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease. Adding of the Ki67 proliferation index to the PSOGI PMP classification provided two different subcategories of the extensive HG-PMP group (HG-PMP ≤15% and HG-PMP >15%) with different survival in a previous unicentric study. This study aims to carry out an external and multicentre validation of this new proposed classification. METHOD: It was a prospective analysis of samples from a historical and international cohort of patients. A representative area with higher cellular density was used to determine the Ki67%. The Ki67 proliferation index (%) was determined in all the HG-PMP patients. A Cox proportional hazard models and multivariable COX models were used. The Kaplan-Meier method and the two-tailed log-rank test were used to analyse the effect of different PSOGI-Ki67 categories on OS and DFS. Its predictive accuracy was analysed using Harrel's C-index and the ROC curve. The calibration was performed using the calibration plots matching. RESULTS: After exclusions, 349 patients were available for analysis. The 5-years OS were 86% for LG-PMP, 59% for HG-PMP≤15, 38% for HG-PMP>15 and 42% for SRC-PMP (p = 0.0001). The 5-years DFS were 49% for LG-PMP, 35% for HG-PMP≤15, 16% for HG-PMP>15 and 18% SRC-PMP (p = 0.0001). The discrimination capability of PSOGI-Ki67 was validated. CONCLUSION: the PSOGI-Ki67 classification discriminates and predicts the OS and DFS in patients with PMP dividing the HG-PMP category into two well-defined sub-categories. The Ki67 proliferation index should be incorporated routinely in the pathology report for these patients.

Metabolic acidosis after ileal urinary diversion and radical cystectomy. Do we know as much as we think we do? A systematic review.

Urine contact with the mucosa of the urinary diversion (UD) after radical cystectomy (RC) produces different ion exchanges that favor the development of metabolic acidosis (MA). This phenomenon is a frequent cause of hospital readmission and short/long-term complications. We performed a systematic review of MA in RCs with ileal UD, analyzing its prevalence, diagnosis, risk factors and treatment. We systematically searched Pubmed® and Cochrane Library for original articles published before May 2022 according to PRISMA guidelines. A total of 421 articles were identified. We selected 25 studies that met the inclusion criteria involving 5811 patients. Obtaining precise data on the prevalence of MA is difficult, largely due to the heterogeneity of the diagnostic criteria used given the diversity of studies analyzed. Development of MA is multifactorial. In the early period, MA is more prevalent in patients with UD with longer ileal segments, better urinary continence, and impaired renal function. Age and diabetes are risk factors associated with MA in later periods. MA is the most common cause of second or more hospital readmissions. Prophylaxis with oral bicarbonate for three months in patients at risk could improve these results. Although MA after ileal UD is a well-known condition, this review highlights the need to implement homogeneous criteria for the diagnosis, follow-up, and treatment, in addition to protocolizing prevention/prophylaxis strategies in patients at risk.

Validation of a Nomogram to Predict Recurrence in Patients with Mucinous Neoplasms of the Appendix with Peritoneal Dissemination After Cytoreductive Surgery and HIPEC.

BACKGROUND: Survival of patients affected by mucinous appendiceal neoplasms with peritoneal dissemination (PD) is mainly related to histopathological features. However, prognostic stratification is still a concern, as the clinical course of the disease is often unpredictable. The aim of this study is to construct and externally validate a nomogram predicting disease-free survival (DFS) in mucinous appendiceal neoplasms with PD treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). PATIENTS AND METHODS: Patients treated in two referral centers were included: Hospital General Universitario Gregorio Marañón, Madrid, Spain (derivation cohort) and Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy (validation cohort). Cox regression analysis identified factors associated with shorter DFS in the derivation cohort. The nomogram performance was externally evaluated in the validation cohort using concordance index and calibration plots. Histology was classified according to the Peritoneal Surface Oncology Group International (PSOGI). RESULTS: The derivation cohort included 95 patients, and the validation cohort 348. Five-year DFS rates were 51.5 and 62%, respectively. Cox regression analysis (derivation cohort) identified PSOGI histology of the peritoneal components, number of preoperative elevated tumor marker, and peritoneal disease extent, as assessed by peritoneal carcinomatosis index, to be predictors of DFS. The model's predictive capacity was higher than that of PSOGI classification alone, with respective concordance indexes of 0.702 ± 0.023 and 0.610 ± 0.018 (validation cohort). The nomogram approximated the perfect model in the calibration plots at 3- and 5-year DFS. CONCLUSIONS: An easy-to-use model that provides better prognostic stratification than histopathological features has been constructed. This nomogram may help clinicians in individualized survival predictions and informed clinical decision-making.

Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer.

PURPOSE: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. DESIGN: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. RESULTS: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82-1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). CONCLUSION: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

Defining stage in mucinous tumours of the appendix with peritoneal dissemination: the importance of grading terminology: systematic review.

BACKGROUND: Mucinous appendiceal neoplasms with peritoneal dissemination (PD) show a wide spectrum of clinical behaviour. Histological grade has been correlated with prognosis, but no universally accepted histological grading has been established. The aim of this systematic review was to provide historical insight to understand current grading classifications, basic histopathological features of each category, and to define which classification correlates best with prognosis. METHODS: MEDLINE and the Cochrane Library were searched for studies that reported survival across different pathological grades in patients with mucinous neoplasm of the appendix with PD treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. PRISMA guidelines were followed. RESULTS: Thirty-eight studies were included. Ronnett's classification was the most common (9 studies). Classifications proposed by the Peritoneal Surface Oncology Group International (PSOGI) (6 studies) and the seventh or eighth edition of the AJCC (7 studies) are gaining in popularity. Nine studies supported a two-tier, 12 a three-tier, and two a four-tier classification system. Three studies demonstrated that acellular mucin had a better prognosis than low-grade pseudomyxoma peritonei in the PSOGI classification or M1bG1 in the eighth edition of the AJCC classification. Four studies demonstrated that the presence of signet ring cells was associated with a worse outcome than high-grade pseudomyxoma peritonei in the PSOGI classification and M1bG2 in the eighth edition of the AJCC. CONCLUSION: There is a great need for a common language in describing mucinous neoplasms of the appendix with PD. Evolution in terminology as a result of pathological insight turns the four-tiered PSOGI classification system into a coherent classification option.

Evaluación del impacto de la pandemia COVID-19 en el diagnóstico y tratamiento de pacientes con cáncer de mama tratadas en Clínica Alemana de Santiago / Evaluation of the impact of the COVID-19 pandemic in the diagnosis and treatment of breats cancer patients at Clínica Alemana de Santiago

Resumen Introducción: Debido a la pandemia COVID-19 se ha visto un retraso en diagnósticos de en-fermedades oncológicas, cambio de tratamientos y aumento en mortalidad. Objetivo: Evaluar efectos de la pandemia en pacientes de Clínica Alemana de Santiago con diagnóstico reciente de cáncer de mama, comparadas con igual periodo año 2019. Materiales y Método: Estudio cuantitativo, retrospectivo, tipo descriptivo. Período 1 de abril - 31 de julio de 2020 comparado con igual periodo de año 2019. Revisión de nuestra base de datos, comparando motivo de consulta, estadio y tratamiento. Análisis estadístico con programa STATA, test T student y test exacto de Fisher. Consideramos significativo p < 0,05. Resultados: Total 156 pacientes, 70 (44,87%) consultaron en periodo señalado año 2020 versus 86 (55,13%) en 2019 (p = 0,1). Edad promedio 55 años versus 58 (p = 0,38). Consulta por nódulo palpable de mama, 25 versus 29 (p = 0,86). Hubo diferencias en pacientes que consultaron por antece-dentes familiares de cáncer de mama, 0 versus 6 (p = 0,033), y en pacientes con antecedente personal de cáncer de mama, 0 versus 6 (p = 0,033). Consulta por control imagenológico fue 39 versus 53 (p = 0,5). En época de pandemia hubo más tumores Her 2, 11 versus 2 (p = 0,006). Por estadios, no hubo diferencia. Por tratamiento indicado, cirugía fue de 49 pacientes versus 71 (p = 0,85). Hormonoterapia neoadyuvante 7 versus 1 (p = 0,058). Conclusiones: En periodo de pandemia hubo menor consulta por cáncer de mama. La mayoría por control imagenológico y lesiones palpables, sin diferencia en estos grupos entre ambos periodos. Hubo menos cirugías y más tratamientos con hormonoterapia neoadyuvante.

Introduction: Due to SARS-CoV-2 pandemic there has been a delay in oncological diagnosis and treatments potentially increasing mortality. Aim: To evaluate the effects of the pandemic in patients treated in Clinica Alemana with recent diagnosis of breast cancer, comparing the reason of consultation, stage and treatment to a similar time frame in 2019. Materials and Method: This is a retrospective, descriptive and quantitative study. Analyzing patients registry from April 1st to July 31st, 2020 compared with same time frame of 2019. Retrospective analysis of our database searching for reason of consultation, stage and treatment. Data analysis using STATA, T student test and Fisher exact test, considering significant a p < 0.05. Results: N156, 70 (44.87%) consultations in the 2020-time frame versus 86 (55.13%) in 2019 (p = 0.1). Mean age 55 years versus 58 (p = 0.38). Palpable tumor 25 versus 29 (p = 0.86). There was a difference in patients consulting due to personal breast oncological background, 0 versus 6 (p = 0.033) or familiar breast oncological background 0 versus 6 (p = 0.033). Breast images control 39 versus 53 (p = 0.5). In Pandemic more Her 2 tumors were diagnosed 11 versus 2 (p = 0.006). No differences in stages were observed. Upfront surgical treatment in 49 versus 71 patients (p = 0.85) and neoadjuvant hormonal treatment 7 versus 1 (p = 0.058). Conclusion: In the pandemic time frame there were less consultations due to breast cancer. The majority of the patients came because of a palpable tumor or breast image control without a significant difference compared with a similar time frame in previous year. There were less surgeries and more neoadjuvant hormonal treatments.

Control and Toxicity in Melanoma Versus Other Brain Metastases in Response to Combined Radiosurgery and PD-(L)1 Immune Checkpoint Inhibition.

PURPOSE: Prior studies have mixed conclusions about the efficacy and central nervous system (CNS) toxicity profile of combining radiosurgery with anti-programed cell death 1 (PD-1) immune checkpoint inhibition (ICI) for brain metastases. This study evaluates the safety and efficacy of combined radiosurgery and anti-PD-1 ICI for melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) brain metastases (BM). METHODS AND MATERIALS: Forty-one patients with 153 radiation naïve melanoma BM and 33 patients with 118 BM of NSCLC and RCC origin from 2014 through 2019 received radiosurgery and either anti PD-1 receptor inhibition or anti PD-L1 inhibition targeting the PD-1 ligand with less than 4 months separating either therapy. Similar to Radiation Therapy Oncology Group 9005, high-grade CNS toxicity was defined as irreversible grade 3 or any grade 4/5 neurologic event. Salvage resection revealing necrosis and viable tumor was considered grade 4 toxicity and local failure. An increase in greatest cross-sectional diameter of 25% on contrasted magnetic resonance imaging was designated as a local failure. RESULTS: Median follow-up was 10 months (range, 1-41 months). Local control was estimated to be 90.3% at 1 year. Distant control was 38.8% at 1 year, and neither local nor distant control were significantly influenced by limiting steroids to the day of treatment (P = .55, .52 respectively). One-year freedom from high-grade toxicity was 90.4% for patients and 94.6% for tumors. Though melanoma accounted for 41 (55%) patients and 153 (56%) tumors, it accounted for all high-grade toxicities (P = .03). These patients had some combination of high tumor burden, aggressive steroid taper, and treatment with ipilimumab. CONCLUSIONS: Stereotactic radiosurgery combined with anti-PD-1 ICI appears to result in a high rate of local tumor control and a low rate of high-grade CNS toxicity, comparable to historical series with radiosurgery alone. High-grade toxicity is more likely in melanoma than RCC and NSCLC. Coming prospective studies will shed light on further questions about treatment timing, steroids, and response.

4-Deoxyphorbol inhibits HIV-1 infection in synergism with antiretroviral drugs and reactivates viral reservoirs through PKC/MEK activation synergizing with vorinostat.

Latent HIV reservoirs are the main obstacle to eradicate HIV infection. One strategy proposes to eliminate these viral reservoirs by pharmacologically reactivating the latently infected T cells. We show here that a 4-deoxyphorbol ester derivative isolated from Euphorbia amygdaloides ssp. semiperfoliata, 4ß-dPE A, reactivates HIV-1 from latency and could potentially contribute to decrease the viral reservoir. 4ß-dPE A shows two effects in the HIV replication cycle, infection inhibition and HIV transactivation, similarly to other phorboids PKC agonists such PMA and prostratin and to other diterpene esters such SJ23B. Our data suggest 4ß-dPE A is non-tumorigenic, unlike the related compound PMA. As the compounds are highly similar, the lack of tumorigenicity by 4ß-dPE A could be due to the lack of a long side lipophilic chain that is present in PMA. 4ß-dPE activates HIV transcription at nanomolar concentrations, lower than the concentration needed by other latency reversing agents (LRAs) such as prostratin and similar to bryostatin. PKCθ/MEK activation is required for the transcriptional activity, and thus, anti-latency activity of 4ß-dPE A. However, CD4, CXCR4 and CCR5 receptors down-regulation effect seems to be independent of PCK/MEK, suggesting the existence of at least two different targets for 4ß-dPE A. Furthermore, NF-κb transcription factor is involved in 4ß-dPE HIV reactivation, as previously shown for other PKCs agonists. We also studied the effects of 4ß-dPE A in combination with other LRAs. When 4ß-dPE A was combined with another PKC agonists such as prostratin an antagonic effect was achieved, while, when combined with an HDAC inhibitor such as vorinostat, a strong synergistic effect was obtained. Interestingly, the latency reversing effect of the combination was synergistically diminishing the EC50 value but also increasing the efficacy showed by the drugs alone. In addition, combinations of 4ß-dPE A with antiretroviral drugs as CCR5 antagonist, NRTIs, NNRTIs and PIs, showed a consistent synergistic effect, suggesting that the combination would not interefer with antiretroviral therapy (ART). Finally, 4ß-dPE A induced latent HIV reactivation in CD4 + T cells of infected patients under ART at similar levels than the tumorigenic phorbol derivative PMA, showing a clear reactivation effect. In summary, we describe here the mechanism of action of a new potent deoxyphorbol derivative as a latency reversing agent candidate to decrease the size of HIV reservoirs.

Substantiation and differential approach to operative treatment of patients with psoriatic arthritis.

OBJECTIVE: The aim: To improve the psoriatic arthritis treatment outcomes by establishing and implementing into practice operative treatment. PATIENTS AND METHODS: Materials and methods: The study basis is represented with the results of examination and treatment of 252 patients with psoriatic arthritis. The biopsy samples from the problem psoriatic eruption and intact skins regions, received from 74 patients, were studied. RESULTS: Results: The study has established presence of Staphylococcus aureus in affected skin regions. The authors present their classification of structural muscular-skeletal disorders associated with psoriatic arthritis, which will substantiate the volume and character of operative interventions. CONCLUSION: Conclusions: Detection of numerous opportunistic pathogenic microorganism colonies stipulates for the necessary skin debridement while planning further operative treatment, aimed at correction of anatomical and biological abnormalities. The operative intervention volume depends on the severity of structural dysfunctions.

Conservative surgery for ovarian torsion in young women: perioperative complications and national trends.

OBJECTIVE: To analyse populational trends and perioperative complications following conservative surgery versus oophorectomy in women <50 years of age with ovarian torsion. DESIGN: Population-based retrospective observational study. SETTING: Nationwide Inpatient Sample in the USA (2001-2015). POPULATION: In all, 89 177 ovarian torsions including 20 597 (23.1%) conservative surgeries and 68 580 (76.9%) oophorectomies. METHODS: (1) Trend analysis to assess utilisation of conservative surgery over time, (2) multivariable binary logistic regression to identify independent factors associated with conservative surgery and (3) inverse probability of treatment weighting with a generalised estimating equation to analyze perioperative complications. MAIN OUTCOME MEASURES: Trends, characteristics and complications related to conservative surgery. RESULTS: Performance of conservative surgery increased from 18.9 to 25.1% between 2001 and 2015 (32.8% relative increase, P = 0.001) but decreased steadily after age 15, and sharply declined after age 35 (P < 0.001). On multivariable analysis, younger age exhibited the largest effect size for conservative surgery among the independent factors (adjusted odds ratios 3.39-7.96, P < 0.001). In the weighted model, conservative surgery was associated with an approximately 30% decreased risk of perioperative complications overall (10.0% versus 13.6%, odds ratio 0.73, 95% confidence interval 0.62-0.85, P < 0.001) and was not associated with venous thromboembolism (0.2 versus 0.3%, P = 0.457) or sepsis (0.4 versus 0.3%, P = 0.638). CONCLUSION: There has been an increasing utilisation of conservative surgery for ovarian torsion in the USA in recent years. Our study suggests that conservative surgery for ovarian torsion may not be associated with increased perioperative complications. TWEETABLE ABSTRACT: Conservative surgery for ovarian torsion may not be associated with increased perioperative complications.

In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation.

Translation is an essential biological process, and dysregulation is associated with a range of diseases including ribosomopathies, diabetes, and cancer. Here, we examine translation dysregulation in vivo using RNAi to knock down the m-subunit of the translation initiation factor eIF3 in the mouse liver. Transcriptome sequencing, ribosome profiling, whole proteome, and phosphoproteome analyses show that eIF3m deficiency leads to the transcriptional response and changes in cellular translation that yield few detectable differences in the translation of particular mRNAs. The transcriptional response fell into two main categories: ribosome biogenesis (increased transcription of ribosomal proteins) and cell metabolism (alterations in lipid, amino acid, nucleic acid, and drug metabolism). Analysis of ribosome biogenesis reveals inhibition of rRNA processing, highlighting decoupling of rRNA synthesis and ribosomal protein gene transcription in response to eIF3m knockdown. Interestingly, a similar reduction in eIF3m protein levels is associated with induction of the mTOR pathway in vitro but not in vivo. Overall, this work highlights the utility of a RNAi-based in vivo approach for studying the regulation of mammalian translation in vivo.

Effects of quinones and nitroazoles on free-radical fragmentation of glycerol-1-phosphate and 1,2-dimyristoyl-glycero-3-phosphatidyl-glycerol.

Effects of quinones and azoles on the formation of steady-state radiolysis products in aqueous solutions of glycerol-1-phosphate and aqueous dispersions of 1,2-dimyristoyl-glycero-3-phosphatidyl-glycerol has been investigated. The data obtained by LC-MS-ESI and spectrophotometric measurements shows that the compounds having quinoid structures, including the antitumor agent doxorubicin, and azoles having nitro groups effectively inhibit free-radical fragmentation of glycerol-1-phosphate and 1,2-dimyristoyl-glycero-3-phosphatidyl-glycerol, decreasing the radiation-chemical yields of either inorganic phosphate or phosphatidic acid respectively. The observed effects of blocking free-radical processes are believed to be related to the ability of the tested compounds to oxidize α-hydroxyl-containing carbon-centered radicals of starting substrates, which give rise to fragmentation reaction. The possibility of using the discovered properties of quinones, doxorubicin and nitroazoles to provide practical solutions in oncological radiotherapy and pathophysiology is discussed.

Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane.

Background: Capecitabine is an approved standard therapy for anthracycline- and taxane-pretreated locally advanced or metastatic breast cancer (BC). Vinflunine has demonstrated single-agent activity in phase II studies in this setting and activity and tolerability when combined with capecitabine. We compared the combination of vinflunine plus capecitabine (VC) with single-agent capecitabine. Patients and methods: Patients with locally recurrent/metastatic BC previously treated or resistant to an anthracycline and resistant to taxane therapy were randomly assigned to either vinflunine (280 mg/m2, day 1) plus oral capecitabine [825 mg/m2 twice daily (b.i.d.), days 1-14] every 3 weeks (q3w) or single-agent oral capecitabine (1250 mg/m2 b.i.d., days 1-14) q3w. The primary end point was progression-free survival (PFS) assessed by an independent review committee. The study had 90% power to detect a 30% improvement in PFS. Results: Overall, 770 patients were randomised. PFS was significantly longer with VC than with capecitabine alone [hazard ratio, 0.84, 95% confidence interval (CI), 0.71-0.99; log-rank P = 0.043; median 5.6 versus 4.3 months, respectively]. Median overall survival was 13.9 versus 11.7 months with VC versus capecitabine alone, respectively (hazard ratio, 0.98; 95% CI, 0.83-1.15; log-rank P = 0.77). No difference in quality of life was observed between the two treatment arms. The most common adverse events (NCI CTCAE version 3.0) in the combination arm were haematological and gastrointestinal. Grade 4 neutropenia was more frequent with VC (12% versus 1% with capecitabine alone); febrile neutropenia occurred in 2% versus 0.5%, respectively. Hand-foot syndrome was less frequent with VC (grade 3: 4% versus 19% for capecitabine alone). Peripheral neuropathy was uncommon in both arms (grade 3: 1% versus 0.3%). Conclusions: Vinflunine combined with capecitabine demonstrated a modest improvement in PFS and an acceptable safety profile compared with capecitabine alone in patients with anthracycline- and taxane-pretreated locally recurrent/metastatic BC. ClinicalTrials.gov: NCT01095003.

Partial DNA-guided Cas9 enables genome editing with reduced off-target activity.

CRISPR-Cas9 is a versatile RNA-guided genome editing tool. Here we demonstrate that partial replacement of RNA nucleotides with DNA nucleotides in CRISPR RNA (crRNA) enables efficient gene editing in human cells. This strategy of partial DNA replacement retains on-target activity when used with both crRNA and sgRNA, as well as with multiple guide sequences. Partial DNA replacement also works for crRNA of Cpf1, another CRISPR system. We find that partial DNA replacement in the guide sequence significantly reduces off-target genome editing through focused analysis of off-target cleavage, measurement of mismatch tolerance and genome-wide profiling of off-target sites. Using the structure of the Cas9-sgRNA complex as a guide, the majority of the 3' end of crRNA can be replaced with DNA nucleotide, and the 5 - and 3'-DNA-replaced crRNA enables efficient genome editing. Cas9 guided by a DNA-RNA chimera may provide a generalized strategy to reduce both the cost and the off-target genome editing in human cells.

The use of morphological study technique for investigation of labial and palatine glands.

INTRODUCTION: Due to the deterioration of environmental conditions that promotes the onset of inflammatory and autoimmune diseases, and the progress in the diagnosis, the frequency of registration of intercurrent pathology of salivary glands has markedly risen in recent years, demonstrating the increased scientific interest in the research of the common and distinctive features of their structure. THE AIM: The paper was aimed at the development of the method of morphological study of human minor salivary (labial and palatine) glands by the use of plastic wax reconstruction to obtain the plastic model of the acini and ducts of human minor salivary glands. MATERIALS AND METHODS: Specimens of the glandular area of the hard palate mucosa and labial mucosa in its middle third have been studied. To gain the objective of the investigation the technique for morphological study of the human minor salivary (labial and palatine) glands is to be developed, encompassing the analysis of the spatial organization of the glandular epithelium of the labial and palatine glands together with blood microcirculatory flow by fixing the obtained specimens of the minor salivary glands in 4% glutaraldehyde solution and osmium tetroxide with subsequent embedding into the Epon-812, staining the serial semi-thin sections with phosphate buffered 0,1% toluidine blue solution, photomacrography of the distinguished boundaries of the investigated structures and obtaining of photoreconstructions. RESULTS AND CONCLUSIONS: Thus, the use of suggested technique enables to obtain the megascopic reconstruction of the acini and ducts of the labial and palatine glands, which can be studied from different sides, getting the full visualization of the shape and size, as well as to explore the glands' inner configuration, the geometry of the lumen of the epithelial excretory ducts, to determine changes in the thickness of the wall, to get a visual representation of the microtopographic interactions between the different parts of blood microcirculatory flow and excretory ducts of the minor salivary glands.

Nanopartículas de CuO y su propiedad antimicrobiana en cepas intrahospitalarias / CuO nanoparticles and their antimicrobial activity against nosocomial strains / Nanopartículas de CuO e sua propriedade antimicrobiana frente a cepas intrahospitalares

Resumen Empleando un prototipo de reactor, se sintetizaron nanopartículas (NPs) de CuO a través del método de precipitación a partir de CuSO25H2O y de Cu(CH3COO)2H2O. Las NPs obtenidas fueron caracterizadas mediante XRD, FT-IR, TEM y SEM. La actividad antimicrobiana de las NPs se determinó mediante el método de difusión en placa, colocando 20 mg de NPs de CuO sobre cuatro cepas intrahospitalarias o nosocomiales aisladas de la Unidad de Cuidados Intensivos de un hospital nacional de Lima norte (Staphylococcus epidermidis, Aerococcus viridans, Ochrobactrum anthropi y Micrococcus lylae). La caracterización de las NPs de CuO demostró que las sintetizadas a partir de acetato (CuO-Acet) presentaron una fase pura de CuO, mientras que las sintetizadas a partir de sulfato (CuO-Sulf) presentaron dos fases, donde la de CuO representó más del 84%. Los dominios cristalinos del CuO-Acet y CuO-Sulf fueron 15 y 19 nm, respectivamente. Los halos de inhibición de las cepas estudiadas fueron mayores para las NPs de CuO-Sulf que para las NPs de CuO-Acet; solo para la cepa Ochrobactrum anthropi se presentaron halos similares para ambos tipos de NPs.

Abstract Using a prototype reactor, CuO nanoparticles (NPs) were synthetized through the precipitation method, starting from CuSO2 5H2O and Cu(CH3COO)2H2O. The obtained NPs were characterized by XDR, FT-IR, SEM, and TEM. The antimicrobial activity of the NPs was determined by the plate diffusion method, placing 20 mg of NPs onto four nosocomial strains obtained from north Lima national hospital Intensive-Care Unit (Staphylococcus epidermidis, Aerococcus viridans, Ochrobactrum anthropic, and Micrococcus lylae). NPs characterization revealed that those synthetized from acetate (CuO-Acet) shown pure CuO phase, while those synthetized from sulphate CuO-Sulf shown two phases where CuO was the predominant one, having more than 84%. The crystal domains for CuO-Acet and CuO-Sulf were 15 and 19 nm, respectively. The inhibition halos for the studied strains were larger for CuO-Sulf NPs than CuO-Acet NPs, only Ochrobactrum anthropi displayed similar inhibition halos for both types of NPs.

Resumo Usando um protótipo de reator, sintetizaram-se nanopartículas (NPs) de CuO pelo método de precipitação a partir de CuSO25H2O e de Cu(CH3COO)2H2O. As NPs obtidas foram caracterizadas por meio das seguintes técnicas: XRD, FT-IR, TEM e SEM. A atividade antimicrobiana das NPs foi determinada pelo método de difusão em placa, colocando 20 mg de NPs de CuO sobre quatro cepas nosocomiais isoladas de uma Unidade de Terapia Intensiva no hospital nacional de Lima norte (Staphylococcus epidermidis, Aerococcus viridans, Ochrobactrum anthropic e Micrococcus lylae). A caracterização das NPs de CuO mostrou que as nanopartículas sintetizadas a partir do acetato (CuO-Acet) apresentavam uma fase pura de CuO, enquanto que as sintetizadas a partir do sulfato (CuO-Sulf), apresentaram duas fases sendo a fase maior de CuO, com mais de 84%. Os domínios cristalinos de CuO-Acet y CuO-Sulf foram 15 e 19 nm, respectivamente. Os halos de inibição das cepas estudadas foram maiores para as NPs de CuO-Sulf do que as NPs de CuO-Acet somente para a cepa Ochrobactrum anthropi, apresentaram-se halos de inibição parecidos.