Tunable control of CAR T cell activity through tetracycline mediated disruption of protein-protein interaction

Chimeric antigen receptor (CAR) T cells are a promising form of cancer immunotherapy, although they are often associated with severe toxicities. Here, we present a split-CAR design incorporating separate antigen recognition and intracellular signaling domains. These exploit the binding between the tetracycline repressor protein and a small peptide sequence (TIP) to spontaneously assemble as a functional CAR. Addition of the FDA-approved, small molecule antibiotic minocycline, acts as an "off-switch" by displacing the signaling domain and down-tuning CAR T activity. Here we describe the optimization of this split-CAR approach to generate a CAR in which cytotoxicity, cytokine secretion and proliferation can be inhibited in a dose-dependent and reversible manner. Inhibition is effective during on-going CAR T cell activation and inhibits activation and tumor control in vivo. This work shows how optimization of split-CAR structure affects function and adds a novel design allowing easy CAR inhibition through an FDA-approved small molecule

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Managing Sacrococcygeal Teratoma in a New Born of a Psychopathic Widow: Case Report

Background: Sacrococcygeal tumors are composite embryonal tumours reflecting any one or more of embryonal/foetal remnants such as germinoma, embryonal carcinoma, teratoma, choriocarcinoma and yolk sac tumors. Teratomas are the commonest variety of these tumours encountered in clinical practice. Sacrococcygeal tumors are most commonly found in females. Male presentations tend to carry high risk of malignancy.Clinical management of sacrococcygeal tumours in males therefore requires more meticulous attention to the details of surgery and follow-ups.Study design: This is a clinical case report of a huge sacrococcygeal tumour highly valued by a mentally deranged mother, which was excised from a three (3) month old baby boy under general anaesthesia in prone position over a three and half hour period. The purpose of the report is to highlight the special challenges in the management of the case not only onaccount of the sheer size of the tumour but also the unusual psychopathic attachment of the mother to her baby's tumour. The accompanying literature review was by both manual and Medline searches.Result: Surgery and postoperative recovery were uneventful. Histology showed tumour variety to be sacrococcygeal teratoma. Patient showed steady progress with each follow-up visit.Conclusion: Sacrococcygeal tumours are rare, but are the commonest tumours of the newborn. Early surgery avoids tendency to malignant transformation and a good follow-up program is necessary for a guarded prognosis.Niger Med J. Vol. 50, No. 3, July – Sept., 2009: 74 – 76.Key words: sacrococcygeal teratoma, germ cell, malignancy, male neonate

Performance Of Livestock Farmers Under Special Programme For Food Security In Ohafia Agricultural Zone, Abia State, Nigeria

Far greater investment in livestock production is essential if food shortages and poverty are to be reduced and progress made towards realizing goals of National Special Programme for food Security in Nigeria. In one location (Ohafia Agricultural Zone) of the programme in Abia State, Nigeria, proportionate random sampling method was used in selecting sixty (60) participating livestock farmers and assessment made on contributions of the innovative package on number of stock, profitability, and factors influencing change in revenue from livestock with the programme. Keeping poultry, and small ruminants offered participants relatively higher profits than keeping pigs. Feeding cost differential, selected breeds of stock, differences in veterinary costs, and number of livestock kept all positively influenced the revenue which farmers made from their product sales in the programme. Participating farmers should reinvest their profits in procuring more improved livestock breeds. Government could further assist the funding agency by subsidizing feed production to bring down the purchase prices as additional encouragement to participating farmers.Keywords: insufficient food, Profit, Differentials, Revenu

Antagonistic threats against supply chain activities are wicked problems

The purpose of this paper is to analysis and present that antagonistic threats against supply chain activities are wicked problems. The research is based on a system-theoretical approach, which emphasizes a holistic view instead of the characteristics of the different parts. The research method used in this paper is deductive desk research. This research is mainly theoretical, and the findings are contributions to the development of theoretical models and understanding in order to further move the scientific understanding about antagonistic threats against supply chain activities. The main reason behind this is the relationship between threats and countermeasures that are complex and contextual depended. There are several types of crime that can be linked to the logistics function and processes. This paper does not address the problems from a legal viewpoint. This paper presented descriptions of four different antagonistic threats, namely theft, terrorism, smuggling and piracy. The nature of these four different antagonistic threats is then analyzed with regards to the wicked problem description, which leads to the conclusion that antagonistic threats are better described as wicked problems.e-published ahead of print</p

Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells

Molecular chaperones are central to cellular protein homeostasis. In mammals, protein misfolding diseases and aging cause inflammation and progressive tissue loss, in correlation with the accumulation of toxic protein aggregates and the defective expression of chaperone genes. Bacteria and non-diseased, non-aged eukaryotic cells effectively respond to heat shock by inducing the accumulation of heat-shock proteins (HSPs), many of which molecular chaperones involved in protein homeostasis, in reducing stress damages and promoting cellular recovery and thermotolerance. We performed a meta-analysis of published microarray data and compared expression profiles of HSP genes from mammalian and plant cells in response to heat or isothermal treatments with drugs. The differences and overlaps between HSP and chaperone genes were analyzed, and expression patterns were clustered and organized in a network. HSPs and chaperones only partly overlapped. Heat-shock induced a subset of chaperones primarily targeted to the cytoplasm and organelles but not to the endoplasmic reticulum, which organized into a network with a central core of Hsp90s, Hsp70s, and sHSPs. Heat was best mimicked by isothermal treatments with Hsp90 inhibitors, whereas less toxic drugs, some of which non-steroidal anti-inflammatory drugs, weakly expressed different subsets of Hsp chaperones. This type of analysis may uncover new HSP-inducing drugs to improve protein homeostasis in misfolding and aging diseases