Immune evasion in cancer: mechanistic basis and therapeutic strategies

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re- emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, deregulated metabolism etc. In this review, we will discuss the advances made towards understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Computer-based rehabilitation for developing speech and language in hearing-impaired children: A systematic review

The purpose of this systematic review was to examine whether online or computer-based technologies were effective in assisting the development of speech and language skills in children with hearing loss. Relevant studies of children with hearing loss were analysed with reference to (1) therapy outcomes, (2) factors affecting outcomes, and (3) publication and methodological quality. The study quality was assessed using the 11-point PEDro scale. The review identified ten studies of relevance to the question of interest. All studies had relatively low PEDro quality scores with only four studies scoring in the mid-range on the scale. For these four studies, computer-based training appeared favourable at the group level. However, the small number of studies found significantly limits the generalizations and indicates the usage of these technologies in this population as an area requiring further rigorous research

Data Engineering

A quorum system is a collection of subsets of servers, every two of which intersect. Quorum systems have been suggested as a tool for concurrency control in replicated databases almost twenty years ago. They promised to guarantee strict consistency and to provide high availability and fault-tolerance in the face of server crashes and network partitions. Despite these promises, current commercial replicated databases typically do not use quorum systems. Instead they use mechanisms which guarantee much weaker consistency, if any. Moreover, the interest in quorum systems seems to be waning even in the database research community. This paper attempts to explain why quorum systems have not fulfilled their old promises, and at the same time to argue why the current state of affairs may change. As technological advances bring new capabilities, and new applications bring new requirements, the time may have come to review the validity of some long standing criticisms of quorum systems. Anothe..

Systematic review of virtual speech therapists for speech disorders

In this paper, a systematic review of relevant published studies on computer-based speech therapy systems or virtual speech therapists (VSTs) for people with speech disorders is presented. We structured this work based on the PRISMA framework. The advancements in speech technology and the increased number of successful real-world projects in this area point to a thriving market for VSTs in the near future; however, there is no standard roadmap to pinpoint how these systems should be designed, implemented, customized, and evaluated with respect to the various speech disorders. The focus of this systematic review is on articulation and phonological impairments. This systematic review addresses three research questions: what types of articulation and phonological disorders do VSTs address, how effective are virtual speech therapists, and what technological elements have been utilized in VST projects. The reviewed papers were sourced from comprehensive digital libraries, and were published in English between 2004 and 2014. All the selected studies involve computer-based intervention in the form of a VST regarding articulation or phonological impairments, followed by qualitative and/or quantitative assessments. To generate this review, we encountered several challenges. Studies were heterogeneous in terms of disorders, type and frequency of therapy, sample size, level of functionality, etc. Thus, overall conclusions were difficult to draw. Commonly, publications with rigorous study designs did not describe the technical elements used in their VST, and publications that did describe technical elements had poor study designs. Despite this heterogeneity, the selected studies reported the effectiveness of computers as a more engaging type of intervention with more tools to enrich the intervention programs, particularly when it comes to children; however, it was emphasized that virtual therapists should not drive the intervention but must be used as a medium to deliver the intervention planned by speech-language pathologists. Based on the reviewed papers, VSTs are significantly effective in training people with a variety of speech disorders; however, it cannot be claimed that a consensus exists in the superiority of VSTs over speech-language pathologists regarding rehabilitation outcomes. Our review shows that hearing-impaired cases were the most frequently addressed disorder in the reviewed studies. Automatic speech recognition, speech corpus, and speech synthesizers were the most popular technologies used in the VSTs