A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.The research leading to these results has received funding from the European Research Council under the European UnionÏs Seventh Framework Programme (FP7/2007–2013)/ ERC grant agreement no. [279337/DOS]. The authors also thank AstraZeneca, the EPSRC, the BBSRC, the MRC and the Wellcome Trust for funding. F.N. and D.L.K. thank the Gates Cambridge. F.N. also thanks Trinity College for a Krishnan-Ang Studentship. D.W. thanks the DFG for a postdoctoral fellowship (WI 4198/1-1). S.B. thanks the Herchel Smith Fund. The authors thank Dr John Davies for X-ray crystallography and Dr Andrew Bond for refinement (both from the University of Cambridge)

Prolonged intralymphatic delivery of dendritic cells through implantable lymphatic ports in patients with advanced cancer

Background: The currently-used modes of administration of immunotherapeutic agents result in their limited delivery to the lymph nodes and/or require repetitive ultrasound-guided nodal injections or microsurgical lymphatic injections, limiting their feasibility. Here, we report on the feasibility and safety of a new method of long-term repetitive intralymphatic (IL) infusion of immune cells, using implantable delivery ports. Methods: Nine patients with stage IV recurrent colorectal cancer underwent complete resection and received autologous dendritic cells (DCs) loaded with killed autologous tumor cells, KLH and PADRE, for up to four monthly cycles. Leg lymphatic vessels were cannulated, connected to 6.6Fr low-profile implantable subcutaneous delivery ports, and used to infuse 12 doses of DC over each 72 h-long cycle (every 6 h), followed by heparin flushes of the cannula-port system (one 72 h-long cycle per month). The patients who opted for alternative route of vaccine administration (2 patients) or whose ports became non-functional between cycles, continued treatment via intranodal (one injection/cycle) or intradermal (four injections/cycle) routes. Results: A total of nine lymphatic cannulations and implantations of subcutaneous delivery ports were attempted in seven patients, with a success rate of eight out of nine (89 %). The average patency of the IL delivery system was 7.5 (±3.2) weeks. All six patients with IL ports successfully completed at least one complete 72 h-long DC infusion cycle (12 injections). Five patients (56 %) completed two full IL cycles (24 IL injections). No patients received more than two IL cycles without replacement of the IL port, due to catheter occlusion and/or local side effects: cellulitis and hematoma. Intranodal and intradermal backup options were used in, respectively, one and two patients. Overall cohort survival was >28 (±25) months. One patient with aggressive recurrent carcinomatosis, who received DC vaccines by intranodal route is alive at > 90 months, without evidence of disease. Conclusions: We conclude that an intermediate-duration IL delivery of multiple doses of immunotherapeutic factors using implantable delivery ports is feasible, highly-tolerable and can be reproducibly performed in cancer patients to administer immune cells, or potentially, other immune factors. However, long-term IL port placement (>7.5 weeks), is not a currently-feasible option. Trial registration:NCT00558051 , registered Nov. 13, 2007

Non-Redundant Spectral Dimensionality Reduction

Spectral dimensionality reduction algorithms are widely used in numerous domains, including for recognition, segmentation, tracking and visualization. However, despite their popularity, these algorithms suffer from a major limitation known as the "repeated Eigen-directions" phenomenon. That is, many of the embedding coordinates they produce typically capture the same direction along the data manifold. This leads to redundant and inefficient representations that do not reveal the true intrinsic dimensionality of the data. In this paper, we propose a general method for avoiding redundancy in spectral algorithms. Our approach relies on replacing the orthogonality constraints underlying those methods by unpredictability constraints. Specifically, we require that each embedding coordinate be unpredictable (in the statistical sense) from all previous ones. We prove that these constraints necessarily prevent redundancy, and provide a simple technique to incorporate them into existing methods. As we illustrate on challenging high-dimensional scenarios, our approach produces significantly more informative and compact representations, which improve visualization and classification tasks

Entangled-State Cycles of Atomic Collective-Spin States

We study quantum trajectories of collective atomic spin states of $N$ effective two-level atoms driven with laser and cavity fields. We show that interesting ``entangled-state cycles'' arise probabilistically when the (Raman) transition rates between the two atomic levels are set equal. For odd (even) $N$, there are $(N+1)/2$ ($N/2$) possible cycles. During each cycle the $N$-qubit state switches, with each cavity photon emission, between the states $(|N/2,m>\pm |N/2,-m>)/\sqrt{2}$, where $|N/2,m>$ is a Dicke state in a rotated collective basis. The quantum number $m$ ($>0$), which distinguishes the particular cycle, is determined by the photon counting record and varies randomly from one trajectory to the next. For even $N$ it is also possible, under the same conditions, to prepare probabilistically (but in steady state) the Dicke state $|N/2,0>$, i.e., an $N$-qubit state with $N/2$ excitations, which is of particular interest in the context of multipartite entanglement.Comment: 10 pages, 9 figure

Oncolytic viruses as therapeutic cancer vaccines

Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity. With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF (such as T-VEC and Pexa-Vec) or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy. Coadministration with a HDAC inhibitor inhibits innate immunity transiently to promote infection and spread of OVs, and significantly enhances anti-tumor immunity and improves the therapeutic index. Local administration or OV mediated-expression of ligands for Toll-like receptors can rescue the function of tumor-infiltrating CD8+ T cells inhibited by the immunosuppressive tumor microenvironment and thus enhances the antitumor effect. Combination with cyclophosphamide further induces ICD, depletes Treg, and thus potentiates antitumor immunity. In summary, OVs properly armed or in rational combinations are potent therapeutic cancer vaccines. © 2013 Bartlett et al.; licensee BioMed Central Ltd

Mucocele of the appendix – a diagnostic dilemma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Mucocele of the appendix secondary to mucinous cystadenoma is a rare clinical finding. Clinical presentation is varied with more than half being asymptomatic.</p> <p>Case presentation</p> <p>We report such a case presenting to the surgeons where initial clinical findings and investigations suggested an ovarian cyst. The patient was subsequently referred to the Gynaecologists for further management. In spite of extensive preoperative investigations, the diagnosis was only made at the time of surgery.</p> <p>Conclusion</p> <p>In women presenting with a right iliac fossa mass and clinical features not indicative of gynaecological pathology, an appendiceal origin should be considered in the differential diagnosis.</p

The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia

BACKGROUND: Recent studies suggest that HMG-CoA reductase inhibitors ("statins") may have beneficial effects for patients at risk for some types of infections. We examined the effect of prior outpatient use of statins on mortality for patients hospitalized with community-acquired pneumonia. METHODS: A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had a chest x-ray consistent with, and had a discharge ICD-9 diagnosis of pneumonia. Subjects were excluded if they were "comfort measures only" or transferred from another acute care hospital. Subjects were considered to be on a medication if they were taking it at the time of presentation. RESULTS: Data was abstracted on 787 subjects at the two hospitals. Mortality was 9.2% at 30-days and 13.6% at 90-days. At presentation 52% of subjects were low risk, 34% were moderate risk, and 14% were high risk based on the pneumonia severity index. In the multivariable regression analysis, after adjusting for potential confounders including a propensity score, the use of statins at presentation (odds ratio 0.36, 95% confidence interval 0.14–0.92) was associated with decreased 30-day mortality. DISCUSSION: Prior outpatient statin use was associated with decreased mortality in patients hospitalized with community-acquired pneumonia despite their use being associated with comorbid illnesses likely to contribute to increased mortality. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect

The response of mental health professionals to clients seeking help to change or redirect same-sex sexual orientation

<p>Abstract</p> <p>Background</p> <p>we know very little about mental health practitioners' views on treatments to change sexual orientation. Our aim was to survey a representative sample of professional members of the main United Kingdom psychotherapy and psychiatric organisations about their views and practices concerning such treatments.</p> <p>Methods</p> <p>We sent postal questions to mental health professionals who were members of British Psychological Society, the British Association for Counselling and Psychotherapy, the United Kingdom Council for Psychotherapy and the Royal College of Psychiatrists. Participants were asked to give their views about treatments to change homosexual desires and describe up to five patients each, whom they has treated in this way.</p> <p>Results</p> <p>Of 1848 practitioners contacted, 1406 questionnaires were returned and 1328 could be analysed. Although only 55 (4%) of therapists reported that they would attempt to change a client's sexual orientation if one consulted asking for such therapy, 222 (17%) reported having assisted at least one client/patient to reduce or change his or her homosexual or lesbian feelings. 413 patients were described by these 222 therapists: 213 (52%) were seen in private practice and 117 (28%) were not followed up beyond the period of treatment. Counselling was the commonest (66%) treatment offered and there was no sign of a decline in treatments in recent years. 159 (72%) of the 222 therapists who had provided such treatment considered that a service should be available for people who want to change their sexual orientation. Client/patient distress and client/patient autonomy were seen as reasons for intervention; therapists paid attention to religious, cultural and moral values causing internal conflict.</p> <p>Conclusion</p> <p>A significant minority of mental health professionals are attempting to help lesbian, gay and bisexual clients to become heterosexual. Given lack of evidence for the efficacy of such treatments, this is likely to be unwise or even harmful.</p