Targeting therapeutic T cells to the bone marrow niche

Anti-cancer immunotherapies aim to mediate a specific response targeting malignant cells without accompanying damage to normal tissue associated with conventional therapies, but induction of T cell differentiation and exhaustion enables successful tumour progression. In this thesis I will explore different means of enhancing the accumulation and function of therapeutic CD8 T cells, as a means of achieving functional cure through persisting immunological memory. I will show that the key features of T cell memory can be imprinted upon CD8+ T cells by enhancing homing to specific organs, enabling privileged access to cell-mediated factors. The interaction between the chemokine receptor CXCR4 and the ligand CXCL12/SDF-1 is required for successful homing of haematopoietic stem cells (HSCs) to stromal niches within the bone marrow (BM). The bone marrow is known to be a unique organ for immunological memory, including memory T cells. I hypothesised that replicating this bone marrow homing interaction in CD8+ T cells would preferentially generate memory T cells. I demonstrate through in vivo imaging and flow cytometric analyses that T cells over-expressing CXCR4 accumulate preferentially in the BM near vascular-associated CXCL12+ cells, retain a less differentiated central memory phenotype despite repeated antigenic stimulation, and produce enhanced effector cytokines on restimulation. Compared to control T cells, these cells demonstrate lower expression of exhaustion and senescence markers, suggesting the capacity for long-term persistence after activation. I go on to show that numerical accumulation and many of these functional attributes are dependent upon cell-extrinsic expression of IL-15Rα. TCXCR4 demonstrate heightened graft-versus-tumour effects in allogeneic bone marrow transplant models of B-cell lymphoma in comparison to control T cells. I provide evidence that this anti-tumour effect is mediated by enhanced functional capacity rather than numerical accumulation or out-competing immunosuppressive populations. In summary, this strategy offers a tractable means of enhancing T cell engraftment, persistence and function, with potential for cross-platform therapeutic applications including anti-cancer immunotherapy

Majoon-E-Piyaz: A Potent Unani Formulation for Premature Ejaculation

Surʻat-e-Inzāl (Premature Ejaculation) is the most prevalent male sexual dysfunction affecting 25 - 40% global population of men. It is a universal disorder and is independent of age, social or marital status. It has a significant impact on both- patients and their partners, causing distress, anxiety and relationship difficulties affecting the quality of life. Several aetiologies have been proposed by various researchers which are not evidence-based but speculative. Accordingly the International Society for Sexual Medicine (ISSM) issued treatment guidelines for Premature Ejaculation (PE) recommending Serotonergic Antidepressants (SSRIs) and Local Anaesthetics (LA) for its management in modern medicine. However, these treatments were not actually developed for PE, and have limitations associated with their off-label use. Furthermore, nearly all the recommended drugs have a wider spectrum of adverse effects and serious drug interactions which sometimes could be fatal. On the other hand, centuries old Unani medicine offers a complete line of treatment for Surʻat-e-Inzāl based on traditional knowledge and experience. Unani physicians devised a large number of poly-herbal recipes which are still in vogue.  Majoon-e-Piyaz (MP) is one of the compound Unani formulations which are in use for the treatment of premature ejaculation since centuries. This article is an attempt to summarize scientific investigations in support of the claim made by Unani physicians regarding Majoon-e-Piyaz (MP).  Keywords: Surʻat-e-Inzāl, Premature Ejaculation, Majoon-e-Piyaz, Unani Medicin

SURʻAT-E-INZĀL (PREMATURE EJACULATION) AND ITS MANAGEMENT BY UNANI MEDICINE

Surʻat-e-Inzāl (Premature Ejaculation) is the most prevalent male sexual dysfunction affecting 25 - 40% global population of men. It is a universal disorder and is independent of age, social or marital status. It has a significant impact on both- patients and their partners, causing distress, anxiety and relationship difficulties affecting the quality of life. Several aetiologies have been proposed by various researchers which are not evidence-based but speculative. Accordingly the International Society for Sexual Medicine (ISSM) issued treatment guidelines for Premature Ejaculation (PE) recommending Serotonergic Antidepressants (SSRIs) and Local Anaesthetics (LA) for its management in modern medicine. However, these treatments were not actually developed for PE, and have limitations associated with their off-label use. Furthermore, nearly all the recommended drugs have a wider spectrum of adverse effects and serious drug interactions which sometimes could be fatal. On the other hand, centuries old Unani medicine offers a complete line of treatment for Surʻat-e-Inzāl based on traditional knowledge and experience. Firstly, various single as well as compound Unani formulations have been in use since long for the treatment of Surʻat-e-Inzāl and found effective and safe. Secondly, the benefits of herbal and other natural products are increasingly being sighted because of their lesser side effects. Keeping the limitations and adverse effects posed by conventional treatment of PE in mind, an attempt has been made in this paper to review the use of age old Unani System of Medicine for the treatment and management of Premature Ejaculation. Keywords: Premature; Ejaculation; Unani; Surʻat-e-Inzāl; Quwwat-e-Masik

CONCEPT AND MANAGEMENT OF WAJA‘AL-MAFᾹSIL (ARTHRITIS) IN UNANI SYSTEM OF MEDICINE

Arthritis is described in Unani system of Medicine under a broad term Waja‘al-Mafāsil which covers entire joint disorders like inflammatory, non-inflammatory, infectious, metabolic and other musculoskeletal disorders. According to Unani concept, the pathological changes in the joints are caused mainly by derangement of humoural (Akhlat) temperament and accumulation of Fasid madda (Morbid material) in the joint spaces. The main principles of treatment in Unani system of Medicine include Ilaj Bil Ghiza (Dieto-therapy), Ilaj Bit Tadbeer (Regimenal therapy) and Ilaj Bid Dawa (Pharmacotherapy). All the said principles are recommended for the treatment of Waja‘al-Mafāsil. The aim of treatment for patient with Waja‘al-Mafāsil is to reduce morbidity and disability. In India it affects 15% (180 million) people. Ancient Unani scholars have elaborately described Waja‘al-Mafāsil and managed with multidimensional approach, where as with the present day management of disease mainly with non-steroidal anti-inflammatory drugs (NSAIDs) which have large number of adverse effects. This review article highlight the salient features describing arthritis with reference to Waja‘al-Mafāsil for empathizing disease condition as enunciated by Unani scholars to provide a better alternative in terms of cost effective managements and side effects. Keywords: Waja‘al-Mafāsil, Arthritis, Joints pain, Unani medicin

Majoon Suranjan: A Potent Unani formulation for Arthritis

 Unani System of medicine is one among the oldest systems that prevails till date with its efficient drugs derived from animal, plant and mineral resources. Over 2400 years ago the father of medicine, Hippocrates practiced it, however His medicine included a great deal of ancient Egyptian medicine as well as important components of the ancient Mesopotamian traditions. In Unani system of medicine, arthritis is described under a broad term Waja-ul-Mafasil which encompasses entire joint disorders like inflammatory, non-inflammatory, infectious, metabolic and other musculoskeletal disorders. A large number of drugs, single and compound formulations, have been mentioned in the context of the treatment of Waja-ul-Mafasil. Among them, Majoon Suranjan is one of the most reputed poly pharmaceutical preparations of Unani system of Medicine used in Waja-ul-Mafasil. It is attributed to Indrumakhas of Greece (Andromachos, the elder, court physician to King Nero) who formulated it in consultation with several other philosophers of his time. This Unani compound formulation contains twenty ingredients, which is used as digestive, purgative, anti inflammatory, stomachic, deobstruent, antiarthritic, nervine tonic. It is also indicated for use in phlegmatic diseases. Keywords: Majoon Suranjan, Ingredients, Arthritis, Unani Medicine

Improved Generalization for Secure Data Publishing

In data publishing, privacy and utility are essential for data owners and users respectively, which cannot coexist well. This incompatibility puts the data privacy researchers under an obligation to find newer and reliable privacy preserving tradeoff-techniques. Data providers like many public and private organizations (e.g. hospitals and banks) publish microdata of individuals for various research purposes. Publishing microdata may compromise the privacy of individuals. To prevent the privacy of individuals, data must be published after removing personal identifiers like name and social security numbers. Removal of the personal identifiers appears as not enough to protect the privacy of individuals. K-anonymity model is used to publish microdata by preserving the individual's privacy through generalization. There exist many state-of-the-arts generalization-based techniques, which deal with pre-defined attacks like background knowledge attack, similarity attack, probability attack and so on. However, existing generalization-based techniques compromise the data utility while ensuring privacy. It is an open question to find an efficient technique that is able to set a trade-off between privacy and utility. In this paper, we discussed existing generalization hierarchies and their limitations in detail. We have also proposed three new generalization techniques including conventional generalization hierarchies, divisors based generalization hierarchies and cardinality-based generalization hierarchies. Extensive experiments on the real-world dataset acknowledge that our technique outperforms among the existing techniques in terms of better utility

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries