Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.

Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery

Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development

<p>Abstract</p> <p>Background</p> <p>SSADH (aldehyde dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1^-/-mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives succinate semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1^-/-embryo development.</p> <p>Methods</p> <p>Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1^+/+and Aldh5a1^-/-) for each gestational age group. Data was evaluated using the <it>t </it>test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95^thcentile.</p> <p>Results</p> <p>GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1^-/-mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA.</p> <p>Conclusion</p> <p>Our findings indicate early GABAergic alterations in Aldh5a1^-/-mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.</p

NGOs and the Promotion of the Sexual and Reproductive Rights of Girls and Young Women with Disabilities in Zimbabwe

This case study investigates strategies used by the NGO Leonard Cheshire Disability Zimbabwe (LCDZ) to promote the SRHRs of girls and young women with disabilities in Zimbabwe. The findings show that LCDZ employed a combination of six strategies. These are: (1) building practical knowledge on SRHRs; (2) increasing community awareness and sensitivity; (3) providing SRHRs-related education; (4) enhancing access to justice and related services for survivors of sexual violence; (5) delivering assistive devices; and (6) promoting the livelihoods and economic empowerment. LCDZ made use of multi-stakeholder partnerships to implement these strategies, leveraging complementary skills and experience in the promotion of SRHRs. In each of these strategies, girls and young women with disabilities are the target group, with other stakeholders brought together to support them

SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND:Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy. METHODS:This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC. RESULTS:412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC &lt; 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC &lt; 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC &lt; 50%, 10.0 months, P = 0.39, respectively). CONCLUSIONS:PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies. Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015

Improving Phrap-Based Assembly of the Rat Using “Reliable” Overlaps

The assembly methods used for whole-genome shotgun (WGS) data have a major impact on the quality of resulting draft genomes. We present a novel algorithm to generate a set of “reliable” overlaps based on identifying repeat k-mers. To demonstrate the benefits of using reliable overlaps, we have created a version of the Phrap assembly program that uses only overlaps from a specific list. We call this version PhrapUMD. Integrating PhrapUMD and our “reliable-overlap” algorithm with the Baylor College of Medicine assembler, Atlas, we assemble the BACs from the Rattus norvegicus genome project. Starting with the same data as the Nov. 2002 Atlas assembly, we compare our results and the Atlas assembly to the 4.3 Mb of rat sequence in the 21 BACs that have been finished. Our version of the draft assembly of the 21 BACs increases the coverage of finished sequence from 93.4% to 96.3%, while simultaneously reducing the base error rate from 4.5 to 1.1 errors per 10,000 bases. There are a number of ways of assessing the relative merits of assemblies when the finished sequence is available. If one views the overall quality of an assembly as proportional to the inverse of the product of the error rate and sequence missed, then the assembly presented here is seven times better. The UMD Overlapper with options for reliable overlaps is available from the authors at http://www.genome.umd.edu. We also provide the changes to the Phrap source code enabling it to use only the reliable overlaps

Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that &gt;70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC

Monitoring of lung edema by microwave reflectometry during lung ischemia-reperfusion injury in vivo

It is still unclear whether lung edema can be monitored by microwave reflectometry and whether the measured changes in lung dry matter content (DMC) are accompanied by changes in PaO(2) and in pro-to anti-inflammatory cytokine expression (IFN-gamma and IL-10). Right rat lung hili were cross-clamped at 37 degrees C for 0, 60, 90 or 120 min ischemia followed by 120 min reperfusion. After 90 min (DMC: 15.9 +/- 1.4%; PaO(2): 76.7 +/- 18 mm Hg) and 120 min ischemia (DMC: 12.8 +/- 0.6%; PaO(2): 43 +/- 7 mm Hg), a significant decrease in DMC and PaO(2) throughout reperfusion compared to 0 min ischemia (DMC: 19.5 +/- 1.11%; PaO(2): 247 +/- 33 mm Hg; p < 0.05) was observed. DMC and PaO(2) decreased after 60 min ischemia but recovered during reperfusion (DMC: 18.5 +/- 2.4%; PaO(2) : 173 +/- 30 mm Hg). DMC values reflected changes on the physiological and molecular level. In conclusion, lung edema monitoring by microwave reflectometry might become a tool for the thoracic surgeon. Copyright (c) 2006 S. Karger AG, Basel

It's the Recipient That Counts: Spending Money on Strong Social Ties Leads to Greater Happiness than Spending on Weak Social Ties

Previous research has shown that spending money on others (prosocial spending) increases happiness. But, do the happiness gains depend on who the money is spent on? Sociologists have distinguished between strong ties with close friends and family and weak ties—relationships characterized by less frequent contact, lower emotional intensity, and limited intimacy. We randomly assigned participants to reflect on a time when they spent money on either a strong social tie or a weak social tie. Participants reported higher levels of positive affect after recalling a time they spent on a strong tie versus a weak tie. The level of intimacy in the relationship was more important than the type of relationship; there was no significant difference in positive affect after recalling spending money on a family member instead of a friend. These results add to the growing literature examining the factors that moderate the link between prosocial behaviour and happiness

Binary orbits as the driver of γ-ray emission and mass ejection in classical novae

Classical novae are the most common astrophysical thermonuclear explosions, occurring on the surfaces of white dwarf stars accreting gas from companions in binary star systems. Novae typically expel �10,000 solar masses of material at velocities exceeding 1,000 km/s. However, the mechanism of mass ejection in novae is poorly understood, and could be dominated by the impulsive flash of the thermonuclear runaway, prolonged optically thick winds, or binary interaction with the nova envelope. Classical novae are now routinely detected in GeV gamma-rays, suggesting that relativistic particles are accelerated by strong shocks in nova ejecta. Here we present high-resolution imaging of the gamma-ray-emitting nova V959 Mon at radio wavelengths, showing that its ejecta were shaped by binary motion: some gas was expelled rapidly along the poles as a wind from the white dwarf, while denser material drifted out along the equatorial plane, propelled by orbital motion. At the interface between the equatorial and polar regions, we observe synchrotron emission indicative of shocks and relativistic particle acceleration, thereby pinpointing the location of gamma-ray production. Binary shaping of the nova ejecta and associated internal shocks are expected to be widespread among novae, explaining why many novae are gamma-ray emitters

Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis

Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites &lt;i&gt;Trypanosoma brucei&lt;/i&gt; (&lt;i&gt;T.b.&lt;/i&gt;) &lt;i&gt;gambiense&lt;/i&gt; or &lt;i&gt;T.b.rhodesiense&lt;/i&gt; and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage &lt;i&gt;T.b.rhodesiense&lt;/i&gt; infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-&#846;-cyclodextrin and melarsoprol randomly-methylated-&#946;-cyclodextrin. We found that these compounds retain trypanocidal properties &lt;i&gt;in vitro&lt;/i&gt; and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy