The safety and efficacy of immune checkpoint inhibitors in patients with advanced cancers and pre-existing chronic viral infections (Hepatitis B/C, HIV): A review of the available evidence.

The treatment paradigm of several cancers has dramatically changed in recent years with the introduction of immunotherapy. Most oncology trials involving immune checkpoint inhibitors (ICIPs) have routinely excluded patients with HIV infection and chronic viral hepatitis B (HBV) and C (HCV) due to concerns about viral reactivation, fears of increased toxicity, and the potential lack of efficacy in these patient subgroups. However, with current antiviral therapies, HIV and HBV infections have become chronic diseases and HCV infections can even be cured. Broadening cancer trial eligibility criteria in order to include cancer patients with chronic viral infections can maximize the ecological validity of study results and the ability to understand the ICPIs' benefit-risk profile in patients with these comorbidities. In this review, we examined the evidence on the efficacy and safety of using ICPIs in cancer patients with concurrent chronic viral infections.

Ultrafast Imaging of Carrier Cooling in Metal Halide Perovskite Thin Films.

Understanding carrier relaxation in lead halide perovskites at the nanoscale is critical for advancing their device physics. Here, we directly image carrier cooling in polycrystalline CH3NH3PbI3 films with nanometer spatial resolution. We observe that upon photon absorption, highly energetic carriers rapidly thermalize with the lattice at different rates across the film. The initial carrier temperatures vary by many multiples of the lattice temperature across hundreds of nanometers, a factor that cannot be accounted for by excess photon energy above the bandgap alone or in variations of the initial carrier density. Electron microscopy suggests that morphology plays a critical role in determining the initial carrier temperature and that carriers in small crystal domains decay slower than those in large crystal domains. Our results demonstrate that local disorder dominates the observed carrier behavior, highlighting the importance of making local rather than averaged measurements in these materials.

Increased risk of strontium ranelate-related SJS/TEN is associated with HLA.

UNLABELLED: Severe adverse drug reactions (ADR) of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) in some patients receiving strontium ranelate have been reported, but the risk factors are unclear. We show that HLA-A*33:03 and B*58:01 are significantly associated with patients who developed SJS/TEN; and provide the first evidence that genetic risk factors are involved in strontium ranelate-associated SJS/TEN. INTRODUCTION: In this study, HLA as a genetic risk factor was assessed among osteoporotic patients prescribed with strontium ranelate that developed severe cutaneous adverse drug reactions (SCARs) compared with those who were tolerant. METHODS: Genomic DNA isolated from peripheral blood mononuclear cells (PBMCs) of patients was HLA typed using sequencing-based typing method to determine their HLA profiles. RESULTS: Osteoporotic patients who are currently on strontium ranelate were enrolled in the study (n = 76). Tolerant controls were defined as patients who received strontium ranelate for a minimum of 3 months (range 3 months to 8 years) with no reports of any cutaneous reactions as these reactions usually occur within the first 12 weeks after starting treatment. Retrospective cases of SJS/TEN were also identified (n = 5). The majority of the accrued samples were of Han Chinese descent: controls (n = 72) and cases (n = 4). All cases and controls were genotyped at four HLA genes, namely HLA-A, HLA-B, HLA-C, and HLA-DRB1. In comparing the samples of Han Chinese descent (72 controls and 4 cases), we found significant associations with HLA-A*33:03 (p = 0.002) and HLA-B*58:01 (p = 0.023). There was no significant association with any HLA-C or HLA-DRB1 alleles. CONCLUSIONS: This study reveals that the occurrence of SJS/TEN in Han Chinese patients receiving strontium ranelate is HLA associated. This has important clinical implications for understanding the underlying mechanisms for this ADR as well as evaluating the potential role of genetic pre-screening for osteoporotic patients who may be prescribed strontium ranelate.

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial.

BACKGROUND: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series.

BACKGROUND: Ipilimumab (Yervoy; Bristol-Myers Squibb) is a novel fully humanised monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4, an immune checkpoint molecule, to augment anti-tumour T-cell responses. It is associated with significant immune-related side-effects including hypophysitis. AIM: We reviewed the clinical and biochemical characteristics of 10 patients with ipilimumab-induced hypophysitis (IH), and developed guidelines for the early detection and management of IH based on our experiences at three major teaching hospitals in Sydney. METHODS: All patients were evaluated at the Crown Princess Mary Cancer Centre and Department of Endocrinology, Westmead Hospital, Department of Endocrinology, Royal Prince Alfred Hospital, the Melanoma Institute Australia and Macarthur Cancer Therapy Centre, Campbelltown Hospital from 2010 to 2014. Relevant data were extracted by review of medical records. Main outcome measures included clinical features, hormone profile and radiological findings associated with IH, and presence of pituitary recovery. RESULTS: Ten patients were identified with IH. In four patients who underwent monitoring of plasma cortisol, there was a fall in levels in the weeks prior to presentation. The pituitary-adrenal and pituitary-thyroid axes were affected in the majority of patients, with the need for physiological hormone replacement. Imaging abnormalities were identified in five of 10 patients, and resolved without high-dose glucocorticoid therapy. To date, all patients remain on levothyroxine and hydrocortisone replacement, where appropriate. CONCLUSIONS: There is significant morbidity associated with development of IH. We suggest guidelines to assist with early recognition and therapeutic intervention.

Giant labial fibroepithelial stromal polyp.

We report an18-year-old girl with a four-year history of a slow-growing labial mass with a sudden increase in size in the last year. Examination revealed a large fleshy 20 cm perineal mass centering on the left labia majora and attached to it by a 1cm pedicle. It was associated with pain, ulceration and discharge. The lesion was excised via diathermy at the base of the stalk. The excised specimen weighed 1.112kg and measured 20.5 x 17 x 5cm. The lesion showed a solid, soft whitish, cut surface. Histology revealed a hypocellular tumour with focally oedematous fibrous stroma in which were scattered large and small blood vessels, mast cells and other chronic inflammatory cells. True myxoid matrix was not observed. The stromal cells had a spindle to stellate morphology. There was no significant cytological atypia, mitotic activity or necrosis. The tumour cells were negative for SMA, desmin, CD34, S100 protein, EMA and PR. The diagnosis was clinically and histologically challenging because various vulvovaginal soft tissue tumours often have overlapping clinicopathological features. However, based on strict histological criteria and the absence of worrisome cytological features, a diagnosis of fi broepithelial stromal polyp was rendered despite the unusual size. A review of the literature shows that whilst vulvovaginal fibroepithelial stromal polyps are well described, giant variants are rare. Awareness of the extraordinary size that can be attained by such polyps can facilitate swift clinical and histological diagnosis.

Proteome profile and lentiviral transduction of cultured honey bee (Apis mellifera L.) cells.

Honey bees (Apis mellifera L.) play a vital role in agriculture as pollinators, and serve as model organisms of social behaviour and immunity. The lack of both immortalized cell lines and methods to introduce recombinant DNA reliably into primary cells hinders cellular and molecular studies in this organism. We hereby demonstrate the expression of a GFP gene delivered by lentivirus transduction to cultured embryonic cells. The success of this approach indicates that viral transduction could be used to deliver constitutively active oncogenes in order to immortalize honey bee cells. We were able to revive cells successfully after several months of cryogenic storage and we show how the proteome varies between freshly collected and cultured embryonic cells.

Long-acting beta2-agonists for poorly reversible chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by partially reversible airflow limitation. Many patients have little reversibility to short acting bronchodilators, but long acting bronchodilators are frequently advocated. OBJECTIVES: To determine the effectiveness of long acting beta-2 adrenoceptor agonists (LABAs) in COPD patients demonstrating poor reversibility to short-acting bronchodilators. SEARCH STRATEGY: The Cochrane Airways Group Specialised Register was searched ('all years' to 2005) along with the reference lists from identified randomised controlled trials (RCTs). SELECTION CRITERIA: All RCTs comparing inhaled LABAs (salmeterol or formoterol) with placebo in the treatment of patients with stable, poorly reversible COPD. Studies were a minimum of four weeks in duration. DATA COLLECTION AND ANALYSIS: Two authors independently performed data extraction and study quality assessment. If we required additional data, we contacted authors and pharmaceutical companies sponsoring the identified RCTs. MAIN RESULTS: Twenty-three published and unpublished studies (6061 participants) were included in the review. There was a significant change in forced expiratory volume in 1 second (FEV1) in favour of salmeterol 50 mcg twice daily (BID) of 51 mls (95% confidence intervals (CI) 32 to 70), end of study morning peak expiratory flow (PEF) 14.89 L/min (95% CI 10.86 to 18.91). Supplemental short-acting bronchodilator usage was reduced by just under one puff per day. There were significant differences in the total, activity and impact domain scores of the St George's respiratory questionnaire in favour of salmeterol 50 mcg BID. Findings from other health status measurements and symptom scores were conflicting. There was no significant difference in exercise tolerance. The number of participants experiencing exacerbations was significantly reduced with salmeterol 50 mcg treatment compared with placebo (numbers needed to treat to benefit 21). AUTHORS' CONCLUSIONS: This review shows that the treatment of patients with COPD with salmeterol 50 mcg produces modest increases in lung function. There were varying effects for other important outcomes such as health related quality of life or reduction in symptoms. However, there was a consistent reduction in exacerbations which may help people with COPD who suffer frequent deterioration of symptoms prompting healthcare utilisation. The strength of evidence for the use of salmeterol 100 mcg, formoterol 12 mcg, 18 mcg, 24 mcg was insufficient to provide clear indications for practice.

Sonomyography: monitoring morphological changes of forearm muscles in actions with the feasibility for the control of powered prosthesis.

Electromyography (EMG) has been widely used for the assessment of musculoskeletal functions and the control of electrical prostheses, which make use of the EMG signal generated by the contraction of the residual muscles. In spite of the successful applications of EMG in different fields, it has some inherent limitations, such as the difficulty to differentiate the actions of neighboring muscles and to collect signals from deep muscles using the surface EMG. The majority of current EMG controlled prostheses can only provide sequential on-off controls using signals from two groups of muscles, so the users are required to put many conscious efforts in monitoring the speed and range of motion of the terminal devices being controlled. Recently, many alternative signals based on the detection of dimensional changes of muscles or tendons during actions have been reported. The objective of this study was to investigate the potential of the dimensional change of muscles detected using sonography for musculoskeletal assessment and control. A portable B-mode ultrasound scanner was used to collect the dynamic ultrasound images of the forearm muscles of six normally limbed young adults and three amputee subjects. A motion analysis system was used to collect the movement of the wrist angle during the experiments for the normal subjects. It was demonstrated that the morphological changes of forearm muscles during actions can be successfully detected by ultrasound and linearly correlated (R(2)=0.876+/-0.042, mean+/-S.D.) with the wrist angle. We named these sonographically detected signals about the architectural change of the muscle as sonomyography (SMG). The mean ratio between the wrist angle and the percentage deformation of the forearm muscle was 7.2+/-3.7 degrees /% for the normal subjects. The intraclass correlation coefficient (ICC) of this ratio among the three repeated tests was 0.868. The SMG signals from the residual forearms were also successfully detected when the three amputee subjects contracted their residual muscles. The results demonstrated that SMG had potentials for the musculoskeletal control and assessment.

Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway.

In atherosclerosis and tumor initiation, inducible nitric oxide synthase (iNOS) has been implicated in the damage of vascular walls and DNA, respectively. Moderate consumption of red wine has been ascribed as a preventive for coronary heart disease; however, there has been much debate over whether the beneficial effect is from grape polyphenolic components or ethanol. We studied the interaction of grape compounds on nitric oxide (NO) production by macrophages, mediators of blood vessel damage in atherosclerosis. For the murine macrophage cell line RAW 264.7, stimulation with lipopolysaccharide and interferon-gamma led to expression of the iNOS gene and production of NO. The polyphenols quercetin and resveratrol at a micromolar range suppressed iNOS gene expression and NO production, as determined by reverse transcription-polymerase chain reaction and nitrite assay. The polyphenols were also found to be scavengers of NO in an acellular system using sodium nitroprusside under physiological conditions. Ethanol, at a moderate level, did not produce any appreciable level of reduction of iNOS or NO activity. However, its presence at 0.1 to 0.75% enhanced the effect of grape polyphenols concentration-dependently. Thus, the interaction between these components plays a significant role in the health effects of red wine, especially with respect to their effect on the NO pathway.

In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties.

Curcumin is a naturally occurring, dietary polyphenolic phytochemical that is under preclinical trial evaluation for cancer preventive drug development and whose working pharmacological actions include anti-inflammation. With respect to inflammation, in vitro, it inhibits the activation of free radical-activated transcription factors, such as nuclear factor kappaB (NFkappaB) and AP-1, and reduces the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and interleukin-8. Inducible nitric oxide synthase (iNOS) is an inflammation-induced enzyme that catalyzes the production of nitric oxide (NO), a molecule that may lead to carcinogenesis. Here, we report that in ex vivo cultured BALB/c mouse peritoneal macrophages, 1-20 microM of curcumin reduced the production of iNOS mRNA in a concentration-dependent manner. Furthermore, we demonstrated that, in vivo, two oral treatments of 0.5 mL of a 10-microM solution of curcumin (92 ng/g of body weight) reduced iNOS mRNA expression in the livers of lipopolysaccharide(LPS)-injected mice by 50-70%. Although many hold that curcumin needs to be given at dosages that are unattainable through diet to produce an in vivo effect, we were able to obtain potency at nanomoles per gram of body weight. This efficacy is associated with two modifications in our preparation and feeding regimen: 1) an aqueous solution of curcumin was prepared by initially dissolving the compound in 0.5 N NaOH and then immediately diluting it in PBS; and 2) mice were fed curcumin at dusk after fasting. Inhibition was not observed in mice that were fed ad lib., suggesting that food intake may interfere with the absorption of curcumin.

Inhibition of inducible nitric oxide synthase gene expression and enzyme activity by epigallocatechin gallate, a natural product from green tea.

Chronic inflammation has been implicated as the underlying factor in the pathogenesis of many disorders. In the past decade, inflammation-related endogenous production of reactive nitrogen species, similar to oxygen free radicals, has also been suggested as a risk factor for cancer, in addition to the well-studied exogenous nitroso compounds. Epidemiological, in vitro, and animal model studies have implicated green tea to be protective against nitroso compound-induced and inflammation-related cancer. Therefore, we investigated the effect of epigallocatechin-3-gallate (EGCG), one of the known biologically active catechins contained in green tea, on the production of nitric oxide (NO.). We have shown previously that EGCG reduces NO. production as measured by nitrite accumulation in the culture medium. Expanding on this finding, in this report we show that EGCG may do so by two mechanisms: reduction of inducible nitric oxide synthase (iNOS) gene expression and inhibition of enzyme activity. Addition of 1-10 microM EGCG to lipopolysaccharide- and interferon-gamma-activated mouse peritoneal cells reduced iNOS mRNA expression concentration dependently, to 82-14%, as measured by relative reverse transcription-polymerase chain reaction. Addition of 50-750 microM EGCG, in a concentration-dependent manner, inhibited the enzyme activity of iNOS, to 85-14%, and neuronal nitric oxide synthase (nNOS), to 93-56%, as measured by citrulline formation. EGCG competitively inhibited binding of arginine and tetrahydrobiopterin, and the gallate structure is important for this action.

Effects of food restriction in military training on T-lymphocyte responses.

In a stress model which included food restriction, we examined the effects of physically rigorous military training and increased caloric intake on T-lymphocyte responses and lymphocyte subsets. T-lymphocyte proliferation and release of soluble receptor for interleukin-2 (slL-2R) in vitro were measured in two separate training classes of male U.S. Army ranger course (RC) trainees at the start and during the RC. Trainees in group 1 (n = 55) and 2(n = 50), respectively, had mean (+/- SD) energy intakes of 11.8 +/- 7.0 and 13.6 +/- 6.7 MJ/d, averaged total daily energy expenditures of 16.7 and 17.6 MJ/d, and experienced body weight losses of 15.]% and 12.6%. Both groups showed decreases T-lymphocyte responses in vitro: proliferation to phytohemagglutinin (PHA) and tetanus toxoid (TT), and released slL-2R to PHA. Group 2 with an intended 15% increase in energy during the RC over group 1 showed 22% and 26% less severe suppressions of T-lymphocyte proliferation and released slL-2R, respectively, in vitro. Group 2 also showed that short-term (9 days) removal of the food restriction stressor allowed for corrected body weight, total lymphocyte and T-lymphocyte subset counts but not suppressed T-lymphocyte responses in vitro. These results demonstrate that soldiers in physically rigorous military training are at risk of suppressed T-lymphocyte immunocompetence, and this is greater if they also experience inadequate energy intake.

Impact of tamoxifen on peripubertal androgen imprinting of rat hepatic cytochrome P450 2C11, cytochrome P450 3A2, and steroid 5 alpha-reductase.

Expression of sex-dependent rat hepatic cytochromes P450 and steroid 5 alpha-reductase is regulated mainly by the sex-specific pattern of growth hormone (GH) secretion and is subject to androgen imprinting. Since tamoxifen suppresses GH pulse amplitude and nadir levels, we investigated the effect of tamoxifen on peripubertal testosterone imprinting of hepatic CYP2C11, CYP3A2, CYP2A1, and steroid 5 alpha-reductase. Prepubertal tamoxifen administration (5 mg once daily s.c. on days 28 and 29 of age) to non-ovariectomized female Sprague-Dawley rats did not affect hepatic microsomal CYP2C11-dependent testosterone 2 alpha-hydroxylase, CYP3A-mediated testosterone 6 beta-hydroxylase, CYP2A1-dependent testosterone 7 alpha-hydroxylase, or steroid 5 alpha-reductase activity in adult rats. Testosterone treatment (5 mumol/kg, s.c., once daily) of intact female rats during either puberty (days 35-49 of age) or adult life (days 69-77 of age) had no effect on these enzyme activities in adult (78-day-old) female rats, but the same treatment given during both of these periods induced the male-specific testosterone 2 alpha- and 6 beta-hydroxylase activities and suppressed the female-predominant testosterone 7 alpha-hydroxylase and steroid 5 alpha-reductase activities, indicating that peripubertal testosterone administration imprints the adult androgen responsiveness but not the basal levels of these enzyme activities in non-ovariectomized female rats. However, peripubertal androgen imprinting of the basal levels of testosterone 2 alpha-hydroxylase and steroid 5 alpha-reductase activities was observed in female rats administered tamoxifen prepubertally. Tamoxifen pretreatment also enhanced testosterone imprinting of the adult androgen responsiveness of testosterone 2 alpha- and 6 beta-hydroxylase and steroid 5 alpha-reductase activities. The enhanced testosterone hydroxylase activities were, however, not associated with an increase in microsomal NADPH-cytochrome P450 reductase activity, but were accompanied by elevated hepatic CYP2C11 and CYP3A2 protein levels. Overall, the present study indicates that prepubertal tamoxifen administration does not interfere with the normal sex differentiation of the gender-dependent hepatic cytochromes P450 and steroid 5 alpha-reductase, but this drug modulates peripubertal androgen imprinting of CYP2C11, CYP3A2, and steroid 5 alpha-reductase in adult female rats.