Monitoring Patient Response to Pembrolizumab With Peripheral Blood Exhaustion Marker Profiles

Exhausted T cells are effector T cells that are silenced due to continuous T cell receptor (TCR) stimulation from persistent antigens. Characteristics of exhaustion include the increased expression of multiple inhibitory receptors such as programme death-1[PD-1], lymphocyte activation gene 3 [LAG-3], T cell Ig and mucin domain [TIM-3], the loss of effector cytokine secretion and altered transcriptional profile. The PD-1/PD-L1 interaction induces functional exhaustion of tumor-reactive cytotoxic T cells and interferes with anti-tumor T cell immunity. T cell exhaustion has been observed in metastatic melanoma patients where the exhaustion of tumor specific T cells suggests that tumor clearance has been impeded and contributed to tumor immune escape. Checkpoint immunotherapies are antibodies designed to block the interaction between the inhibitory receptors expressed on T cells and their respective ligands. Therapies such as anti-PD-1 (Pembrolizumab and Nivolumab) block these inhibitory receptors and are associated with a significant improvement in overall survival and progression free survival. However, only 20–40% of metastatic melanoma patients experience long-term benefit. In a cohort of 16 metastatic melanoma patients receiving pembrolizumab, blood was serially collected before each infusion (mean 8.3; range 1–12 cycles). The presence of inhibitory markers LAG-3, TIM-3, and PD-1 on the surface of T cells was examined and assessed in relation to patient response to identify if inhibitory markers can be used to differentiate responders from non-responders for Pembrolizumab. We confirmed that across a range of cycles (range 1–26) of pembrolizumab, PD-1 expression was significantly higher on CD4+ T cells from non-responders compared to responders and TIM-3 expressed on the surface of CD8+ T cells was significantly higher in non-responders compared to responders. This longitudinal data confirms previous studies that assessed single timepoints. This study provides preliminary evidence that PD-1 and TIM-3 may be predictive of non-responders when assessed over multiple treatment cycles

A cytotoxic bis(1,2,3-triazol-5-ylidene)carbazolide gold(III) complex targets DNA by partial intercalation

The syntheses of bis(triazolium)carbazole precursors and their corresponding coinage metal (Au, Ag) complexes are reported. For alkylated triazolium salts, di- or tetranuclear complexes with bridging ligands were isolated, while the bis (aryl) analogue afforded a bis(carbene) AuI -CNC pincer complex suitable for oxidation to the redox-stable [AuIII(CNC) Cl]+ cation. Although the ligand salt and the [AuIII(CNC)Cl]+ complex were both notably cytotoxic toward the breast cancer cell line MDA-MB-231, the AuIII complex was somewhat more selective. Electrophoresis, viscometry, UV-vis, CD and LD spectroscopy suggest the cytotoxic [AuIII(CNC)Cl]+ complex behaves as a partial DNA intercalator. In silico screening indicated that the [AuIII(CNC)Cl]+ complex can target DNA three-way junctions with good specificity, several other regular B-DNA forms, and Z-DNA. Multiple hydrophobic πtype interactions involving T and A bases appear to be important for B-form DNA binding, while phosphate O···Au interactions evidently underpin Z-DNA binding. The CNC ligand effectively stabilizes the AuIII ion, preventing reduction in the presence of glutathione. Both the redox stability and DNA affinity of the hit compound might be key factors underpinning its cytotoxicity in vitro.https://chemistry-europe.onlinelibrary.wiley.com/journal/15213765pm2021ChemistryPhysiolog

Binding pose analysis of hydroxyethylamine based β-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors

β-Secretase (BACE1) is recognised as a target for the treatment of Alzheimer’s disease, and transition-state isosteres such as hydroxyethylamines have shown promise when incorporated into BACE1 inhibitors. A computational investigation of previously reported carbazole-based hydroxylethylamines with contradictory binding poses was undertaken using molecular dynamic simulations to rationalise the ligands preferred binding preference. Visual inspection of the confirmed binding pocket showed unoccupied space surrounding the carbazole moiety which was probed through the synthesis of seventeen ligands wherein the carbazole ring system was replaced with an indeno[1,2-b]indole ring system. The most active compound, rac-1- [benzyl(methyl)amino]-3-(indeno[1,2-b]indol-5(10H)-yl)propan-2-ol, indicated an inhibition of 91% at 10 µM against β-secretase with a cytotoxicity IC50 value of 10.51 ± 1.11 µM against the SH-SY5Y cell line.This work was supported by the National Research Foundation (NRF) of South Africa (Thuthuka grant number 106959), the University of Pretoria (Research and Development Program) and the Council for Scientific and Industrial Research (CSIR), South Africa.The National Research Foundation (NRF) of South Africa, the University of Pretoria (Research and Development Program) and the Council for Scientific and Industrial Research (CSIR), South Africa.http://www.arkat-usa.orgpm2021ChemistryPharmacologyPhysiolog

Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915)

PURPOSE Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma. PATIENTS AND METHODS In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for <= 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup. RESULTS At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients. CONCLUSION Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment

The development of a genetic counselling program to identify, test and manage families at risk for inherited colorectal cancer

MSc (Med), Faculty of Health Sciences, University of the Witwatersrand, 200

South African higher education institutions as learning organisations : a leadership process model

Thesis (PhD)--Stellenbosch University, 2002.ENGLISH ABSTRACT:Reform is one of the most controversial elements in higher education and has therefore attracted much attention from within the academic community and from outside. The present higher education scene is characterised by demands for transformation and change, not only in South Africa but in Africa and the developed countries as well. The pressures and demands for change come from outside the field of higher education as well as from within. Some countries have been involved in the process of change and transformation for a period of over thirty years, while others have just embarked on the route or still have to start the change process. The post-apartheid era has marked an era of profound change for South African higher education institutions with concomitant legislation to ensure the change process. If effective and successful transformation of higher education institutions and systems can take place in South Africa with new models of transformation and the effective integration of cultures and openness to change at all institutional levels, these models could be instructive not only to Africa but also to the rest of the world and to academic life universally. However, the demands for change worldwide indicates not only towards new legislation but also towards flexible approaches and new forms of institutional structures and leadership to accommodate the significant, rapid and fundamental changes taking place in higher education and the realisation that institutions of the future will be different from those of the past and the present. In this study the influence of organisational models are used to establish a conceptual framework towards the development of learning organisations. The study reflects on how these new types of organisations will influence higher education institutions as organisations. It also considers what will be expected of higher education institutions to become learning organisations. Learning organisations have special qualities and higher education institutions or teaching institutions do not automatically qualify as learning organisations. The promise of the new millennium provides the higher educationcommunity with the opportunity to take stock of their position and to find out if they possess the necessary skills and have the enabling structures to accommodate a new world. Becoming a learning organisation involves more than a paradigm shift for higher education institutions. It requires a revolution, a quantum leap towards individual recognition and growth, leadership development and empowerment and institutional learning. The Academic 'Process Leadership' Super structure provides the space, structure and process for higher education organisations to re-organise and re-create itself to fit the demands of a new world. An analysis of leadership, leadership development and institutional change in higher education institutions brought to the fore that these institutions have not been effective in providing programmes that develop leaders because they simply do not know what is necessary for effective leadership development. Institutions do not have an in-depth understanding of leadership and they have not enculturated leadership development as a core aspect and activity in higher education institutions. There is grave concern regarding the development of 'soft' people skills. The qualitative research investigation into the process of change towards learning organisations in higher education institutions indicate that there are profound problems in the areas of leadership, leadership development, people management and satisfaction, knowledge management and learning dynamics. These areas form the core aspects within the new structures, that of learning organisations. The insights gained from the process analysis of five higher education institutions indicate that the implementation of the academic leadership model as described in the study will provide individual leaders with the necessary leadership skills to fulfill their roles in the recreated empowered institutions. This process of leadership development, as indicated in the study, could enable institutions to become learning organisations.AFRIKAANSE OPSOMMING:Die huidige konteks van hoer onderwys dui daarop dat verandering een van die belangrikste, maar ook mees kontroversiele aspekte aangaande die studieveld is. Die hoeronderwysomgewing asook hoeronderwysinstellings verkeer onder geweldige druk van beide binne en buite die akademiese gemeenskap om te verander. 'n Analise van die huidige stand van sake en konteks van hoeronderwysinstellings dui daarop dat verandering nie net in Suid-Afrika 'n faktor is en baie aandag geniet nie, maar dat Afrika sowel as die ontwikkelde lande ook onder geweldige druk verkeer om te transformeer. Sommige lande is al vir meer as dertig jaar betrokke by die proses van verandering. Dit wil egter voorkom dat sommige van die ander lande Of nog glad nie begin het nie 6f pas begin het met die proses van verandering en transformasie. Die tydperk na 1994 en die oorgang na 'n nuwe demokratiese regenng m Suid- Afrika was ook die begin van dramatiese verandering in die Suid-Afrikaanse hoeronderwysomgewing. Die kwessie van verandering is nie net in sekere nasionale beleidsdokumente aangespreek nie, maar ook in meegaande wetgewing. Indien Suid-Afrikaanse hoeronderwysinstellings in staat sou wees om nuwe modelle te kan akkommodeer en te kan verwesenlik terwyl hulle besig is met die transformasieen veranderingsproses, kan hierdie modelle van nut en van waarde wees, nie net vir Afrika nie, maar ook vir die ontwikkelde wereld en die internasionale hoeronderwysgemeenskap. Nuwe strukture en modelle kan ongelukkig nie net deur wetgewing daargestel word nie. Instellings sal toeganklik moet wees vir moontlike nuwe vorms van leierskap, leierskapsontwikkeling en die konsep van veranderde strukture om sodoende te kan aanpas by die eise van 'n voortdurend veranderende wereld en die geweldige impak wat verandering op hoeronderwysinstellings het. Hoeronderwysinstellings sal moet besef dat instansies wat op die toekoms gerig word nie kan vashou aan ou uitgediendemodelle nie. Toekomsgerigte modelle verskil van die huidige vorms, sowel as die van die verlede. Die invloed van organisasiemodelle op hoeronderwysinstellings verskaf konseptuele verwysingsraamwerke vir die ontwikkeling van nuwe begrippe en konsepte. Die konsepte help om rigting aan te dui en te bepaal wat van instansies verwag word om sodoende te kan verander na lerende organisasies. Dit is belangrik om kennis te neem dat lerende organisasies spesifieke eienskappe het en dat hoeronderwysinstellings nie sonder meer gereken en geklassifiseer kan word as lerende organisasies nie. Hierdie nuwe vorm van organisasiestruktuur sal 'n fundamentele invloed he op institusionele prosesse asook op die manier waarop instellings in die toekoms bedryf sal word. In die nuwe millennium sal hierdie paradigmaskuif die geleentheid aan hoeronderwysinstellings voorsien om nie net revolusioner te verander nie maar ook om 'n kwantumsprong te maak na die belangrike mens- en leervaardighede. Hierdie vaardighede is nie net noodsaaklik vir die ontwikkeling om 'n lerende organisasie te word nie, dit maak ook die kern uit van hierdie nuwe organlsaSles. Die proses van akademiese leierskap en leierskapsontwikkeling, soos wat voorgestel word in die model van die Akademiese Leierskapsproses Superstruktuur sal aan instellings die geleentheid bied om die noodsaaklike leierskapsvaardighede te ontwikkel. Dit sal ook die kreatiewe en innoverende omgewing skep wat dit vir hierdie soort organisasie strukture moontlik sal maak om nuut te kan ontwikkel en sodoende in staat sal stel om te kan herorganiseer binne 'n konteks van groter aanpasbaarheid. Hierdie kwalitatiewe studie en navorsingsanalise ten opsigte van leierskap, leierskapsontwikkeling en die proses van verandering en transformasie het aangedui dat hoeronderwysinstellings in Suid-Afrika nie effektief ontwikkel ten einde lerende organisasies te word nie. Die ondersoek dui daarop dat instellings nie die onderliggende elemente van die begrip "leierskap" verstaan nie. Leierskap en leierskapsontwikkeling maak tans nie deel uit van die huidige institusionele kultuur nie

An academic leadership model for transformation towards learning organisations in higher education

Thesis (M.Phil.) -- University of Stellenbosch, 1998.ENGLISH SUMMARY: The pressures and demands for change and transformation are not bounded by national borders or geography and the complex challenges facing higher education call for a diversity of viewpoints and approaches. Institutional leadership must adjust to realize the full potential of institutions. Leaders will have to look beyond their own self - interest and meet the emotional needs of followers and find a radically new understanding of what it is to be effective. The study indicates that higher education institutions must have the will and the ability to adjust and respond to rapid change. It will be the responsibility of the leader(s) to define reality, to have an understanding of the past, the present and the future. Leading requires a refocusing of the mind, that includes fundamental beliefs, knows what it aspires to and where it is going to. Organisations have become so complicated that conditions must be created that are flexible enough that they can create a value system and learning culture that will inspire employees to participate enthusiastically, and at the same time enable and empower followers and individual leaders. However, before leaders can lead others, they must learn to lead themselves. Leaders have to understand that self - leadership is the power that drives new "boundaryless organizations." Such strategies help to create organisational culture where people value strong leadership and strive to create it. For higher education institutions to be able to survive the next millennium, they will have to strive for empowering their workforce and becoming learning organisations. Employees must experience the aliveness of a learning organisation, of something that has to do with the "whole"(Senge, 1990:339;371). The format of the study is that of a literature review of the leadership, transformation and learning organisations disciplines for the purpose to identify patterns and regularities to provide a systematic representation to be able to create a model. The model for academic leadership to accommodate change and transformation provides the institutional culture for leadership development and becoming learning organisations. The model gives a "(w)holistic" viewpoint on how leadership development in institutions can create the "space" to become, not only, learning organisations, but boundaryless organisations as well.AFRIKAANSE OPSOMMING: Geografiese ligging en grense is nie 'n voorvereiste vir die druk en eise vir verandering en trartsfonnasie van die komplekse uitdagings wat hoer onderwys in diegesig staar nie.Om die uitdagings te kan hanteer, is dit nodig om verskillende uitgangspunte en beskouinge te oorweeg. Institusionele leierskap sal moet aanpas om sodoende die volle potensiaal van instansies te kan bereik. Leiers sal yerby hulle eie selfgesentreerheid moet kyk om sodoende aan die emosionele behoeftes van hul volgelinge te kan voldoen. Terselfdertyd sal 'n radikale nuwe begrip gevind moet word om te weet wat effektiwiteit is. Die studie dui aan dat hoer onderwysinstellings die wil en die vennoe moet he om te kan aanpas om sodoende op vinnige verandering te kan reageer. Dit sal die verantwoordelikheid van die leier(s) wees om die kundigheid te he om die realiteite te kan identifiseer en om begrip te he van die verlede, die hede en wat die toekoms inhou. Om leiding te kan gee vereis om opnuut te kan fokus en nuut te kan dink oor, onder andere, fundamentele uitgangspunte, waama gestrewe word en waarheen dit kan lei. Die gekompliseerdheid van organisasies vereis dat 'n omgewing geskep moet word, wat so aanpasbaar is dat spesifieke waardes en 'n kultuur van leer ingestel kan word. Die getransfonneerde omgewing moet werknemers inspireer om op 'n entoesiastiese wyse deel te neem en deel te wees van die veranderde omgewing. Dit moet ook terselfdertyd die volgelinge en individuele leiers bemagtig, asook die geleentheid bied tot selfontwikkeling. Leiers moet egter eers leer om hulleself te lei voordat hulle aan ander leiding kan gee. Leiers moet bewus wees daarvan dat om jouself te kan lei die mags basis en dryfveer is vir nuwe "grenslose organisasies". Hierdie strategiee kan help om 'n organisasieklimaat en -kultuur te skep waar werknemers streef na sterk leierskap en terselfdertyd die waarde van leierskap hoog ago Hoer onderwysinstansies sal dus daama moet streef om werknemers te bemagtig en om lerende organisasies te ontwikkel om te kan oorleefin die volgende eeu. Werkememers moet die skeppende en lewegewende gevoel van lerende organisasies ervaar, waar die individu 'n deel van die "geheel" vorm (Senge, 1990:339;371). Die studie bestaan uit 'n literateuroorsig met betreking tot drie studievelde: transformasie, leierskap en lerende org'anisasies, om sodoende patrone en ooreenkomste te kan vasstel om 'n sistematiese uiteensetting en die ontwikkeling van 'n model te kan gee. Die model vir akademiese leierskap vir die doel van transformasie en verandering voorsien die geleentheid vir die ontwikkeling van 'n institusionele kultuur van leierskap en lerende organisasies. Die model gee 'n holistiese beskouing van hoe leierskap en die ontwikkeling van leierskap die "ruimte" bewerkstellig om lerende organisasies en grenslose organisasies te skep.Maste

A study of promotion and assessment policies with particular reference to the transitional period in South Africa

Thesis (M. Ed.) -- University of Stellenbosch, 1996.One copy microfiche.Full text to be digitised and attached to bibliographic record

Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma

Abstract Background Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma. Methods To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction. Results Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin. Conclusions Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma