Study Protocol of the Bladder Adjuvant RadioTherapy (BART) Trial: A Randomised Phase III Trial of Adjuvant Radiotherapy Following Cystectomy in Bladder Cancer.

AIMS: To assess the efficacy and safety of adjuvant radiotherapy in patients with high-risk muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC) and chemotherapy. MATERIALS AND METHODS: The BART (Bladder Adjuvant RadioTherapy) trial is an ongoing multicentric, randomised, phase III trial comparing the efficacy and safety of adjuvant radiotherapy versus observation in patients with high-risk MIBC. The key eligibility criteria include ≥pT3, node-positive (pN+), positive margins and/or nodal yield <10, or, neoadjuvant chemotherapy for cT3/T4/N+ disease. In total, 153 patients will be accrued and randomised, in a 1:1 ratio, to either observation (standard arm) or adjuvant radiotherapy (test arm) following surgery and chemotherapy. Stratification parameters include nodal status (N+ versus N0) and chemotherapy (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy). For patients in the test arm, adjuvant radiotherapy to cystectomy bed and pelvic nodes is planned with intensity-modulated radiotherapy to a dose of 50.4 Gy in 28 fractions using daily image guidance. All patients will follow-up with 3-monthly clinical review and urine cytology for 2 years and subsequently 6 monthly until 5 years, with contrast-enhanced computed tomography abdomen pelvis 6 monthly for 2 years and annually until 5 years. Physician-scored toxicity using Common Terminology Criteria for Adverse Events version 5.0 and patient-reported quality of life using the Functional Assessment of Cancer Therapy - Colorectal questionnaire is recorded pre-treatment and at follow-up. ENDPOINTS AND STATISTICS: The primary endpoint is 2-year locoregional recurrence-free survival. The sample size calculation was based on the estimated improvement in 2-year locoregional recurrence-free survival from 70% in the standard arm to 85% in the test arm (hazard ratio 0.45) using 80% statistical power and a two-sided alpha error of 0.05. Secondary endpoints include disease-free survival, overall survival, acute and late toxicity, patterns of failure and quality of life. CONCLUSION: The BART trial aims to evaluate whether contemporary radiotherapy after standard-of-care surgery and chemotherapy reduces pelvic recurrences safely and also potentially affects survival in high-risk MIBC.

Quantification of physiological and mental workloads of faster and slower finishers of a long-distance military training activity.

BACKGROUND: Long-distance runs with equipment are practised in military training establishments to develop physical stamina and prepare for battles. A study was planned to quantify and compare the physiological and mental workloads of the early and late finishers of a military endurance run through the jungle terrain of north-eastern India in hot and humid conditions. METHODS: Twenty-five soldiers of the Indian Army completed a 15 km run through a rural and jungle track with 6.5 kg of equipment. Twelve participants who finished the race before 130 min were categorised as 'early finishers', and 13 were categorised as 'late finishers' who finished the race after 130 min. Physiological parameters, viz., heart rate (HR), breathing rate (BR), estimated core temperature (ECT), peak acceleration (PAC), and physiological intensity (PHYI) and mechanical intensity (MECHI) were recorded using BioHarness V.3 (Zephyr Technologies, USA) and NASA Task Load Index scores were obtained to assess mental workload. Mann-Whitney U test was applied to assess the level of significance at a p value of <0.05. RESULTS: HR, ECT and PAC were significantly higher (167.9 and 156.0 beats/min, 39.0℃ and 38.4℃, and 1.1 and 1.0 g, respectively) for the first group compared with the second group. The second group expressed higher BR and subjective responses ('total scores' were 76.5 and 82.5, respectively) than the first. The PHYI was significantly higher (from 7.2 to 6.3) for the first group, whereas the MECHI was similar in both groups. CONCLUSION: The successful completion by the first group can be attributed to their motivation to continue heavy work in an adverse environment, and their ability to negotiate with natural obstacles was reflected through controlled subjective responses. Adoption of a possible safe and stable approach to the same task might have led the second group to take a longer duration, exert higher mental effort and demand lower physiological cost.

Socioeconomic and geographic differences in ablation of atrial fibrillation in Norway - a national cohort study.

BACKGROUND: The aim of this study was to analyse whether there are patient related or geographic differences in the use of catheter ablation among atrial fibrillation patients in Norway. METHODS: National population-based data on individual level of all Norwegians aged 25 to 75 diagnosed with atrial fibrillation from 2008 to 2017 were used to study the proportion treated with catheter ablation. Survival analysis, by Cox regression with attained age as time scale, separately by gender, was applied to examine the associations between ablation probability and educational level, income level, place of residence, and follow-up time. RESULTS: Substantial socioeconomic and geographic variation was documented. Atrial fibrillation patients with high level of education and high income were more frequently treated with ablation, and the education effect increased with increasing age. Patients living in the referral area of St. Olavs Hospital Trust had around three times as high ablation rates as patients living in the referral area of Finnmark Hospital Trust. CONCLUSIONS: Differences in health literacy, patient preference and demands are probably important causes of socioeconomic variation, and studies on how socioeconomic status influences the choice of treatment are warranted. Some of the geographic variation may reflect differences in ablation capacity. However, geographic variation related to differences in clinical practice and provider preferences implies a need for clearer guidelines, both at the specialist level and at the referring level.

Impact of Adjuvant Treatment in pN3 Penile Cancer.

AIMS: Due to the lack of high-quality evidence and consensus on adjuvant treatment for locoregionally advanced penile cancer, we reviewed the outcomes of pN3 patients to determine the suitable adjuvant treatment options. PATIENTS AND METHODS: All consecutive pN3 penile cancer patients treated at our institution between January 2010 and December 2018 were reviewed to assess the impact of demographical, pathological and treatment factors on disease-free survival (DFS) and overall survival. The DFS and overall survival were estimated using the Kaplan-Meier method and association was tested using the Cox regression model (two-sided test with P < 0.05 considered significant). RESULTS: Of 128 patients, 31 (24%) had pelvic nodal involvement. Twenty-six patients (20.3%) received no adjuvant treatment, 40 (31.3%) received single modality adjuvant treatment and 62 (48.4%) received multimodality adjuvant treatment (a combination of chemotherapy and radiotherapy). At a median follow-up of 22 months, the DFS and overall survival were 55.4 and 62%, respectively. The best DFS and overall survival was noted with chemotherapy followed by concurrent chemoradiation (C-CTRT; 93% each). On multivariate analysis, both DFS and overall survival were worse with pelvic node involvement (2.2 [1.3-4], P = 0.027 and 2.2 [1.3-4], P = 0.027, respectively) and better with any adjuvant treatment (single modality: 3 [1.5-5.5], P < 0.001; multimodality: 3.1 [1.6-6], P < 0.001). C-CTRT was associated with improved DFS over chemotherapy alone (0.17 [0.4-0.78], P = 0.02) but not over radiotherapy alone (0.35 [0.07-1.6], P = 0.19). In patients with no pelvic nodes involved, chemotherapy and radiotherapy as single modalities were associated with similar DFS and overall survival. In patients with pelvic nodes, multimodality treatment was associated with better DFS than single modality treatment (0.3 [0.1-1], P = 0.05). CONCLUSION: pN3 penile cancer is a diverse prognostic group with poorer outcomes associated with pelvic nodes. Single modality adjuvant treatment may be adequate in inguinal nodes with extranodal extension, but multimodality treatment should be given in patients with pelvic nodal involvement.

Radiotherapy for Post-Chemotherapy Residual Mass in Advanced Seminoma: A Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography-Based Risk-adapted Approach.

AIMS: There is a lack of consensus regarding the management of post-chemotherapy residual mass in classical seminoma. The use of fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) may aid the detection of residual masses harbouring viable disease and help to tailor therapy. The aim of this study was to evaluate if PET-CT could identify patients who will benefit from locoregional radiotherapy. MATERIALS AND METHODS: This ethics-approved study included patients with advanced classical seminoma primarily treated with standard platinum-based first-line chemotherapy. Patients were either observed or given adjuvant radiotherapy based on the clinician's preference and followed up. For this study, patients were stratified into two groups based on FDG PET-CT residual nodal maximum standardised uptake value (SUVmax): low risk (SUVmax <3) and high risk (SUVmax ≥3). Further subgroup analysis was carried out for patients with residual nodal size ≥3 cm and SUVmax ≥3, and this was considered as the very high risk group. The diagnostic accuracy of FDG PET-CT was assessed and survival was compared between the different groups. RESULTS: Sixty-nine patients were included in the study: 48 patients were observed and 21 received radiotherapy. The low and high risk groups contained 50.7% and 49.3% of the patients, respectively. The very high risk subgroup had 24 patients. At a median follow-up of 44 months, locoregional failures in the radiotherapy and observation cohorts were 0% and 30% (P = 0.059) in the very high risk subgroup and 5.8% and 29.4% (P = 0.078) in the high risk group. The positive predictive value for the very high risk and high risk groups was 30% and 17.1%, respectively. The benefit of locoregional control failed to translate into overall survival benefit. CONCLUSION: A tailored, FDG PET-based risk-adapted treatment approach can refine the management of post-chemotherapy residual masses in seminoma. In this study, with the largest cohort of advanced seminoma patients treated with radiotherapy reported to date, radiotherapy seems to benefit patients with post-chemotherapy residual mass SUVmax ≥3.

Heat-induced endoplasmic reticulum stress in soleus and gastrocnemius muscles and differential response to UPR pathway in rats.

The present study aimed to investigate the differential response of oxidative (soleus) and glycolytic (gastrocnemius) muscles to heat-induced endoplasmic reticulum (ER) stress. It was hypothesized that due to compositional and functional differences, both muscles respond differently to acute heat stress. To address this, male Sprague Dawley rats (12/group) were subjected to thermoneutral (25 °C) or heat stress (42 °C) conditions for 1 h. Soleus and gastrocnemius muscles were removed for analysis post-exposure. A significant increase in body temperature and free radical generation was observed in both the muscles following heat exposure. This further caused a significant increase in protein carbonyl content, AOPP, and lipid peroxidation in heat-stressed muscles. These changes were more pronounced in heat-stressed soleus compared to the gastrocnemius muscle. Accumulation of unfolded, denatured proteins results in ER stress, causing activation of unfolded protein response (UPR) pathway. The expressions of UPR transducers were significantly higher in soleus as compared to the gastrocnemius muscle. A significant elevation in resting intracellular calcium ion was also observed in heat-stressed soleus muscle. Overloading of cells with misfolded proteins in soleus muscle activated ER-induced apoptosis as indicated by significant upregulation of C/EBP homologous protein and Caspase12. The study provides a detailed mechanistic representation of the differential response of muscles toward UPR under heat stress. Data suggests that soleus majorly being an oxidative muscle is more prone to heat stress-induced insult indicated by enhanced apoptosis. This study may aid in devising mitigation strategies to improve muscle performance under heat stress.

Adaptive Radiotherapy for Carcinoma of the Urinary Bladder: Long-term Outcomes With Dose Escalation.

AIMS: To report long-term outcomes with dose-escalated, image-guided adaptive radiotherapy (ART) for bladder preservation in muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: All MIBC patients receiving bladder-preserving ART at our institute from 2009 to 2018 were analysed. For ART, three anisotropic planning target volumes (PTV) were concentrically grown around the simulation bladder volume. A library of intensity-modulated radiotherapy plans was created for each patient. A total dose of 64 Gy in 32 fractions to the entire bladder and 55 Gy to pelvic nodes was planned, with 68 Gy to the tumour bed (2 Gy equivalent dose = 68.7 Gy, α/ß = 10) as simultaneous integrated boost for solitary tumours. The most appropriate PTV encompassing the bladder ('plan-of-the-day') was chosen daily using on-board megavoltage imaging. Neoadjuvant and concurrent chemotherapy was prescribed for medically fit patients. RESULTS: Of a total of 106 patients, most had T2 (68%) or T3 (19%) disease. Ninety-two patients (87%) completed 64 Gy to the whole bladder. Sixty-three patients (59%) received 68 Gy as tumour bed boost. Seventy-six per cent received concurrent weekly chemotherapy. At a median follow-up of 26 months, 3-year locoregional control, disease-free survival and overall survival were 74.3, 62.9 and 67.7%, respectively. Eighty-two per cent of patients retained disease-free bladder. Radiation Therapy Oncology Group grade III/IV acute genitourinary and gastrointestinal toxicities were 7.5% and 0%, respectively, and late genitourinary/gastrointestinal toxicities were 6.5% and 3.8%, respectively. Overall survival, disease-free survival, locoregional control and grade III/IV genitourinary/gastrointestinal toxicities did not differ significantly with dose escalation. CONCLUSION: Plan-of-the-day ART is clinically safe and effective for bladder preservation and can be implemented in routine clinical practice. A high bladder preservation rate is achievable without compromising on survival or toxicities. Dose escalation does not seem to affect outcomes.

Pattern of changes in salicylic acid-induced protein kinase (SIPK) gene expression and salicylic acid accumulation in wheat under cadmium exposure.

Salicylic acid-induced protein kinase (SIPK) is known as a 'master switch' for stress responses in plants. It can be induced by salicylic acid (SA) and several stress factors. The main aim of the present study was to reveal the relationship between SA accumulation and the gene expression level of SIPK during 50 and 250 µm Cd stress in wheat plants. Quantitative real-time PCR was used for determination of the gene expression level of SIPK. Salicylic acid content measurement was performed with an HPLC system equipped with a fluorescence detector. Cadmium treatment increased the endogenous SA level and expression level of SIPK in a concentration-dependent manner. Induction of SIPK expression preceded the accumulation of endogenous SA. Although SA treatment induced dramatic endogenous SA accumulation, its SIPK-inducing effect was moderate. In roots, higher induction of SIPK was observed than in leaves. The same tendency of SIPK expression was observed in both Cd- and SA-treated plants, as decisively the highest transcript level was detected after 30 min of treatment, but thereafter the expression decreased rapidly to control level or even below. The induction of SIPK was transient in all cases, and even a very high SA level in either the leaves or roots was not able to maintain the elevated expression level of this gene. The results suggest that SIPK has a role in initiating Cd stress response and the exogenous SA-induced signalling process.

Cortical Thickness and Cognitive Performance After Out-of-Hospital Cardiac Arrest.

BACKGROUND: Cognitive impairment is common in long-term survivors of out-of-hospital cardiac arrest (OHCA) but corresponding neuroimaging data are lacking. OBJECTIVES: This study explored the relationship among the cortical brain structure, cognitive performance, and clinical variables after OHCA. METHODS: Three months after resuscitation, 13 OHCA survivors who had recovered from a coma to living independently and 19 healthy controls were assessed by cerebral magnetic resonance imaging and neuropsychological tests quantifying memory, fine-motor coordination, and attention/executive functions. Cortical thickness (Cth) and surface area (SA) were compared between groups and analyzed for relationships with cognitive performance as well as the clinical variables of coma duration and the time to return of spontaneous circulation (ROSC). All analyses were controlled for age and sex. RESULTS: Analyses of SA revealed no significant differences. Compared with controls, survivors had significantly reduced memory and fine-motor coordination and significantly thinner cortex in large clusters in the frontal, parietal, and inferior temporal cortices, with additional regions in the left occipital lobe and the left temporal lobe. Widespread thinner cortical regions were significantly associated with decreased memory performance in survivors when compared with those in controls and were significantly associated with an increased time to ROSC and increased coma duration in the OHCA group. Increased coma duration, but not increased time to ROSC, was significantly correlated with cognitive test performance. CONCLUSIONS: The results suggest that widespread Cth reductions correspond to the cognitive impairments observed after OHCA. Neuroimaging studies of long-term OHCA survivors are warranted to guide the development of diagnostics and treatment options.

Assessment of vibration exposure and physiological responses of crew members during Infantry Combat Vehicle (ICV) operation: a pilot study.

BACKGROUND: Operation of infantry combat vehicle (ICV) influences the cardiorespiratory responses as well as the risk of vibration exposure on the crew members which adversely affect their performance and health. AIM: To assess the effect of stress factors, that is, ICV's compartmental temperature, relative humidity (RH) and vehicular vibration on the physiological parameters (heart rate (HR), respiratory frequency (RF), estimated core body temperature (ECT)) of the crew members during the ICV operation. METHODS: A 1 hour run trial of the ICV operation was conducted with its crew members at their respective positions. Compartmental temperature and RH were monitored at an interval of every 15 min during the run trial. Physiological parameters were monitored continuously during the run trial. Whole body vibration (WBV) and hand-arm vibration (HAV) of the crew members were also measured during the run trial time. RESULTS: The findings showed a strong positive correlation (p<0.05) between the increasing compartmental temperature and RH with its run trial time. Significant changes were observed in the physiological parameters (p<0.05) along with the increasing run trial time. Additionally, the physiological parameters showed a strong positive correlation with compartmental temperature and RH, respectively (p<0.05). Also, a significant increase (p<0.05) in the muscle strength was recorded after their exposure to ICV operation. The study also confirmed high level of WBV exposure of the crew members during the ICV operation. CONCLUSION: Increase in HR, RF and ECT along with increase in temperature and RH is a predictive indicator of physiological stress. Moreover, high levels of vibration exposure of various operations may bring deleterious effect on soldiers' health as well as their performance. Proper ergonomic intervention can reduce exposure to vibration, physiological stress and increase comfort which may ultimately ensure an optimum performance of soldiers and successful completion of mission.

Memory performance, global cerebral volumes and hippocampal subfield volumes in long-term survivors of Out-of-Hospital Cardiac Arrest.

AIM: We explored the associations between global brain volumes, hippocampal subfield volumes and verbal memory performance in long-term survivors of out-of-hospital cardiac arrest (OHCA). METHODS: Three months after OHCA, survivors and healthy, age-matched controls were assessed with cerebral MRI and the California Verbal Learning Test-II (CVLT-II). Volumetric brain segmentation was performed automatically by FreeSurfer. RESULTS: Twenty-six OHCA survivors who were living independently in regular homes at the time of assessment and 19 controls participated in the study. Thirteen of the survivors had been conscious upon arrival to the emergency department. The other 13 survivors had 0.5-7 days of inpatient coma before recovery. Memory was poorer in the OHCA group that had been comatose beyond initial hospital admission compared to both other groups. Total cortical volumes, total hippocampus volumes and several hippocampal subfield volumes were significantly smaller in the OHCA group comatose beyond initial hospital admission compared to controls. No significant differences between the OHCA group conscious upon emergency department arrival and the other two groups were found for brain volumes. No significant differences were observed between any groups for white matter or total subcortical volumes. In OHCA survivors with recovery from inpatient coma, the various CVLT-II trials were significantly, but differentially, correlated to total gray matter volume, cortical volume and the hippocampal subfield subiculum. CONCLUSION: In this small, single-site study, both hippocampal volume and cortical volume were smaller in good outcome OHCA survivors 3 months after resuscitation in comparison to healthy controls. Smaller cerebral volumes were correlated with poorer memory performance.

Influence of socio-economic status and television watching on childhood obesity in Kolkata.

Obesity is fast becoming an epidemic among the urban children and it has its adverse effect on the status of health even during adulthood. In this paper an attempt is made to assess the percentage of obesity among 6-10 year children and assess the effect of different socio-economic variables and TV watching on childhood obesity. We restricted our study to primary school-going children who attended classes I-IV. The sample consisted of 5216 children from 20 different Bengali medium and English medium schools in Kolkata. Categorical logistic regression of obesity on the socio-economic factors namely type of medium school, religion, parent's education, duration of television watching etc., has been carried out. The categorical logistic regression shows the significant effect of some of the socio-economic or demographic variables including the duration of television watching on obesity. We have seen a positive association between obesity and TV watching and also between obesity and consumption of fast food. This calls for making the parents aware and taking action as early as possible.

Salicylic acid seed priming instigates defense mechanism by inducing PR-Proteins in Solanum melongena L. upon infection with Verticillium dahliae Kleb.

Salicylic acid (SA) is a hormone connected with various cellular functions including the fight against invading pathogens. Priming of seeds pre-sowing is a very simple method to the farmers' to produce better growth, yield and manage the pathogens. The present study was aimed to determine the growth and disease resistance ability in brinjal seeds primed with different concentrations (0.25, 0.5, 0.75 and 1.0 mM) of SA under greenhouse conditions. Priming of seeds with SA significantly increased seed germination and seedling vigor with a maximum of 84% and 859.18, respectively at 0.5 mM concentration. Seed priming with SA also reduced Verticillium wilt incidence to 39.25% (at 0.5 mM) under greenhouse conditions and also enhanced the vegetative growth parameters of the plant compared to control. The induced resistance obtained with SA was in line with higher expression of PR-protein (ß-1,3-glucanase and chitinase) related defense enzymes. Further, an increase of 1.7, 2.9, 2.1, 2.5 and 2-fold increase in gene expression of IAA27, MPK1, GPX, chitinase and ß-1,3-glucanase, respectively were observed in SA primed challenge inoculated seedlings than non-primed susceptible inoculated controls. The higher expression of IAA27, MPK1, GPX, chitinase and ß-1,3-glucanase correlates with the plant growth promoting and disease protection studies as these genes are vital for increasing plant growth and inducing resistance during host-pathogen interaction. Enhanced activation of defense-related activities in plants upon priming with SA suggests that it alters plant physiology which in turn is useful for production and protection of brinjal.

Polygenic study of endurance-associated genetic markers ACE I/D, ACTN3 Arg(R)577Ter(X), CKMM A/G NcoI and eNOS Glu(G)298Asp(T) in male Gorkha soldiers.

BACKGROUND: Gorkhas, a sub-mountainous population of the Himalayan region, are known for strength and bravery. In the present study when "Gorkha" is used without brackets, we are mentioning Gorkhas of Tibeto-Burman origin. Physical capability, strength and endurance are important components of fitness associated with genetic traits. The aim of this study was to examine the endurance potential of male Gorkha soldiers, based on endurance-related genetic markers ACE I/D, ACTN3 Arg (R)577Ter(X), CKMM A/G NcoI and eNOS Glu(G)298Asp(T). METHODS: Genotypic and allelic frequencies were determined in 374 male Gorkha soldiers (Tibeto-Burman). These frequencies were compared with frequencies obtained from Gorkha (Indo-Aryan), high-altitude natives (Tibeto-Burman) and Indian lowlanders (Indo-Aryan). "Total genotype score" (TGS) was calculated from accumulated combination of polymorphisms with maximum value "100" for theoretically "optimal" polygenic score. Probability of occurrence of "optimal" endurance profile was also determined. RESULTS: ACE II genotypic frequency was highest in Tamangs followed by Gurungs, Rais, Limbus and Magars. No statistical difference in genotypic and allelic frequency of ACTN3 Arg(R)577Ter(X) was noted within the groups. Rais showed the highest CKMM A allele frequency (0.908) compared to other Gorkha (Tibeto-Burman) groups. Limbus and Tamangs showed the highest eNOS G allele frequency (0.938 and 0.915, respectively) compared to that of other groups. Probability of male Gorkha soldiers possessing a theoretically optimal polygenic endurance profile for four candidate polymorphisms was ~3.35% (1 in 30). Four percent of the population of male Gorkha soldiers (15 in 374) exhibited an optimal TGS 100, and 16% exhibited TGS 87 for endurance compared to male Indian soldiers belonging to the lowland (Indo-Aryan) and Gorkha (Indo-Aryan) populations suggesting an overall more "favourable" polygenic profile in the male Gorkha soldier (Tibeto-Burman) population. CONCLUSIONS: This study presents evidence of higher frequency of endurance-associated genes in the Gorkhas implying thereby that such genetically endowed individuals from the population may be selected and trained for achieving excellence in endurance-related elite sports activities.

An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia.

Antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells largely contributes to the success of monoclonal antibody (mAb) treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (MLs), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against MLs. When comparing different available CD133 mAbs, no difference was observed with regard to binding to primary chronic myeloid leukemia cells. However, clone 293C3 recognized acute myeloid leukemia (AML) cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wild-type Fc part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE). In vitro, treatment with 293C3-SDIE significantly enhanced activation, degranulation and lysis of primary CD133-positive AML cells by allogeneic and autologous NK cells as compared with its wild-type counterpart. In line with the observed lower expression levels of CD133 on healthy cells compared with malignant hematopoietic cells, 293C3-SDIE caused no relevant toxicity towards committed hematopoietic progenitor cells. In a NOD.Cg-PrkdcscidIL2rgtmWjl/Sz xenotransplantation model, 293C3-SDIE facilitated elimination of patient AML cells by human NK cells. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound, in particular for elimination of minimal residual disease in the context of allogeneic stem cell transplantation in AML.

Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus.

Clinical studies have revealed that testosterone supplementation had a positive effect on glucose homeostasis in type 2 diabetes mellitus (T2DM), but did not address how testosterone supplementation affected insulin responsiveness in the liver, a key glucose homeostatic organ. In this study, we aimed to study the effect of testosterone supplementation on hepatic insulin responsiveness and glucose homeostasis through liver in male high-fat diet-induced T2DM mice. Testosterone treatment to T2DM animals showed reduced hepatic glucose output. Testosterone inhibited the insulin signaling in liver, thus increased insulin resistance. However, testosterone treatment inactivated GSK3α independent of PI3K/AKT pathway and inhibited FOXO1 By interaction of androgen receptor to FOXO1 and downregulated PEPCK, causing repression of gluconeogenic pathway, which is otherwise upregulated in T2DM, resulted in better glucose homeostasis.

Alterations in cognitive outcome between 3 and 12 months in survivors of out-of-hospital cardiac arrest.

OBJECTIVES: To prospectively investigate cognitive recovery from 3 to 12 months after resuscitation from out-of-hospital cardiac arrest (OHCA) and the associations between cognitive performance at 3 months and health-related quality of life (HRQL), psychological distress and work status after 12 months. METHODS: At both assessments, neuropsychological tests were used to measure aspects of general mental ability, verbal and visual memory, psychomotor speed and executive function. The Short Form-36 (SF-36) was used to measure mental and physical HRQL, and the Hospital Anxiety and Depression Scale (HADS) to assess psychological distress. RESULTS: 33 survivors completed both exams (31 males, mean age 58.6 years, SD=13). The OHCAs were witnessed and due to cardiac origins. Nine patients were awake at admission to the hospital. Longer coma duration was associated with poorer cognitive results. Memory impairments were the most common symptom. The mean changes and effect sizes indicated minor improvements in cognitive performance from 3 to 12 months (Hedges g≤.26). Reliable change indices for an individual's results further confirmed the stability of the group statistics. The HADS scores showed increased depressive symptoms, and mental HRQL was reduced from 3 to 12 months. Higher reports of psychological distress were related to worse HRQL. Work participation increased. Better cognitive results at 3 months were correlated with better HRQL and return to work at 12 months. CONCLUSIONS: The current data describe stability in results from 3 to 12 months. A worse cognitive performance at 3 months and higher reports of psychological distress were associated with lower HRQL.

Weekly versus Three-Weekly Cisplatin-based Concurrent Chemoradiotherapy as definitive treatment in Head and Neck Cancer- Where do we stand?

PURPOSE: To compare toxicity, compliance, and early response of weekly and 3-weekly cisplatin administration concurrent with radiotherapy as definitive treatment in locally advanced squamous cell carcinoma head and neck. MATERIALS AND METHODS: Patients with histologically proven stage III - IV B head and neck carcinoma presenting from June 2013 to March 2014 were randomly assigned to weekly (35 mg/m2, 6 cycles; arm A) and 3 weekly (100 mg/m2, 3 cycles; arm B) cisplatin with concurrent radiotherapy. RESULTS: 60 patients were randomly assigned to treatment, 30 in each arm. Median follow-up was 8 months (range 4-13). There was no significant difference in grade 3 mucositis between the two arms (75.9% vs 70%, p = 0.20). Grade 3 neutropenia was more frequent in arm B (55.2% vs 26.7%, p = 0.01). Hypomagnesemia was the commonest electrolyte imbalance and it was significantly higher in arm B (60% vs 20%, p = 0.001). Completion rate of scheduled chemotherapy cycles was higher for patients receiving weekly regimen. Response at 3 months was similar for all the patients {Complete Response (66.7% vs 62.1%), p = 0.200}. Our data suggested that there is a reduced need of hospitalization and supportive care measures for patients receiving weekly cisplatin with RT (p = 0.05). CONCLUSIONS: Weekly cisplatin 35 mg/m2 chemotherapy concurrent with radiotherapy is equally effective and less toxic in terms of neutropenia, hypomagnesemia and need for supportive measures than the conventional 3 weekly cisplatin 100 mg/m2 regimen.