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Andrew P South

Publications and source records attributed to Andrew P South.

14 recordsLinked to original sources
PubMed2025

Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis.

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.

Tumor Microenvironment↗
PubMed2005

The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial.

OBJECTIVE: The purpose of this research was to study the effects on the physiologic pain response of the neonate during circumcision with the use of a gloved human finger. STUDY DESIGN: This was a randomized controlled trial analyzing the effect of non-nutritive sucking (NNS) on pain response during circumcision. Term neonates were randomized to 2 groups. All infants received oral Tylenol and a dorsal penile nerve block (DPNB) before the circumcision. The study group was offered the addition of NNS before the DPNB and throughout the procedure. The primary outcome measured was heart rate during the circumcision. Other variables studied included crying time and salivary cortisol levels. Each circumcision was filmed to calculate pain profile scores using the Premature Infant Pain Profile. Variables were compared using Student t test, chi-square, and Wilcoxon test. A P value of < .05 was considered significant. RESULTS: Forty-four infants met inclusion criteria. Twenty-two infants were randomized to each arm. No difference in mean heart rate during the procedure was apparent. A significant decrease in crying time, 90-minute post-procedure salivary cortisol level, and post-penile clamping pain score was noted in the study group (all P values < .01). CONCLUSION: NNS significantly decreases some elements of measurable physiologic pain response of the neonate during circumcision. This method is a useful and inexpensive addition to DPNB and oral analgesics.

Circumcision, Male↗
PubMed2004

Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome.

Kindler syndrome (OMIM 173650) is a rare autosomal recessive disorder characterized by trauma-induced blister formation (especially in childhood) and photosensitivity. Other features include mucocutaneous scarring and progressive poikiloderma. There is also an increased risk of skin and mucous membrane malignancy. The disorder was recently mapped to 20p12.3 and pathogenic mutations were identified in a new gene, KIND1. This gene encodes a 677 amino acid protein, kindlin-1, a component of focal contacts in keratinocytes. In this study, we identified four new recurrent mutations in KIND1 in 16 individuals with Kindler syndrome from 13 families of Pakistani (676insC), UK Caucasian (E304X), Omani (W616X), or Italian (958-1G > A) origins. Haplotype analysis demonstrated common ancestral mutant alleles for each mutation, apart from one of the six Pakistani families in which the mutation 676insC (which occurs in a repeat of seven cytosines) was present on a different genetic background. All mutations were homozygous, apart from the three UK Caucasian cases that were all compound heterozygotes (second allele mutations: L302X, 1161delA, 1909delA). All mutations were associated with markedly reduced or absent skin immunostaining with an antikindlin-1 antibody. These loss-of-function KIND1 mutations demonstrate the importance of kindlin-1 in maintaining epithelial integrity, although the mechanism linking this mutant protein to photosensitivity and poikiloderma remains to be determined. Delineation of these recurrent mutations is also relevant to optimizing mutation detection strategies in Kindler syndrome patients from particular ethnic backgrounds.

Adult↗
PubMed2004

Reduced expression of insulin-like growth factor-binding protein-3 (IGFBP-3) in Squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa.

Squamous cell carcinoma (SCC) is a common complication in individuals with recessive dystrophic epidermolysis bullosa (RDEB). For the severe Hallopeau-Siemens subtype, the mortality rate from SCC is over 55% by the age of 40 y. Currently, little is known about the molecular pathology or cell biology of SCC in RDEB. In this study, we compared gene expression in RDEB SCC (n=3) and non-EB SCC (n=3) with corresponding RDEB and non-EB peri-tumoral skin, with microarray analysis using DermArray membranes as well as semi-quantitative and real-time RT-PCR. Both tumor sets showed downregulation of epidermal differentiation markers (e.g., profilaggrin, keratins 1 and 10) as well as certain pro-apoptotic genes (e.g., death-associated kinase-3 or ZIP kinase). Likewise, in both groups there was upregulation of matrix metalloproteinase 1 and laminin 5 in the tumors. But we found that the expression of insulin-like growth factor-binding protein-3 (IGFBP-3) was lower (mean of 5.8-fold) in RDEB SCC compared with non-EB SCC. These data were verified by immunohistochemistry. IGFBP-3 has an important role in cancer cell apoptosis mediated via the nuclear retinoid X receptor alpha (RXRalpha). Reduced expression of IGFBP-3 in RDEB SCC may provide a partial explanation for the aggressive behavior and poor prognosis of these tumors in this genodermatosis.

Carcinoma, Squamous Cell↗
PubMed2004

Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus.

Lichen sclerosus is a common, acquired chronic inflammatory skin disease of unknown etiology, although circulating autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been detected in most patients' sera. We have examined the nature of ECM1 epitopes in lichen sclerosus sera, developed an ELISA system for serologic diagnosis, and assessed clinicopathological correlation between ELISA titer and disease. Epitope-mapping studies revealed that lichen sclerosus sera most frequently recognized the distal second tandem repeat domain and carboxyl-terminus of ECM1. We analyzed serum autoantibody reactivity against this immunodominant epitope in 413 individuals (95 subjects with lichen sclerosus, 161 normal control subjects, and 157 subjects with other autoimmune basement membrane or sclerosing diseases). The ELISA assay was highly sensitive; 76 of 95 lichen sclerosus patients (80.0%) exhibited IgG reactivity. It was also highly specific (93.7%) in discriminating between lichen sclerosus and other disease/control sera. Higher anti-ECM1 titers also correlated with more longstanding and refractory disease and cases complicated by squamous cell carcinoma. Furthermore, passive transfer of affinity-purified patient IgG reproduced some histologic and immunopathologic features of lichen sclerosus skin. This new ELISA is valuable for the accurate detection and quantification of anti-ECM1 autoantibodies. Moreover, the values may have clinical significance in patients with lichen sclerosus.

Animals↗
PubMed2003

Autoantibodies to extracellular matrix protein 1 in lichen sclerosus.

BACKGROUND: Lichen sclerosus is a common acquired inflammatory disorder of skin and mucous membranes. The aetiology is unknown, although HLA-subtype susceptibility and high rates of other autoimmune disorders suggest that autoantibodies to specific mucocutaneous antigens are involved. The clinicopathological similarities between lichen sclerosus and lipoid proteinosis, which results from mutations in extracellular matrix protein 1 (ECM1), suggest this protein as an autoantigen. METHODS: We analysed serum autoantibody profiles in 171 individuals (86 with lichen sclerosus, 85 healthy controls) by immunoblotting of extracts from normal human skin and lipoid proteinosis skin (lacking ECM1). We generated a full-length glutathione-S-transferase fusion protein for ECM1 to confirm specific immunoreactivity. We affinity-purified serum from patients with lichen sclerosus and did indirect immunofluorescence microscopy on normal skin with or without preabsorption with recombinant ECM1. FINDINGS: By immunoblotting, IgG autoantibodies were found in 20 (67% [95% CI 45-84]) of 30 lichen sclerosus serum samples. The highest titre was 1 in 20. The bands were not detected in ECM1-deficient substrate. These samples, and those from 56 other patients with lichen sclerosus, showed immunoreactivity to the recombinant ECM1 protein (64 of 86 positive; 74% [65-84]). Only six (7% [2-13]) of 85 control serum samples were positive. Affinity-purified IgG from serum of patients with lichen sclerosus labelled skin similarly to a polyclonal antibody to ECM1. The positive staining was blocked by preabsorption with excess recombinant ECM1 protein. INTERPRETATION: These findings provide evidence for a specific humoral immune response to ECM1 in lichen sclerosus and offer insight into disease diagnosis, monitoring, and approaches to treatment.

Adult↗
PubMed2003

Lack of plakophilin 1 increases keratinocyte migration and reduces desmosome stability.

Ablation of the desmosomal plaque component plakophilin 1 underlies the autosomal recessive genodermatosis, skin fragility-ectodermal dysplasia syndrome (OMIM 604536). Skin from affected patients is thickened with increased scale, and there is loss of adhesion between adjacent keratinocytes, which exhibit few small, poorly formed desmosomes. To investigate further the influence of plakophilin 1 on keratinocyte adhesion and desmosome morphology, we compared plakophilin 1-deficient keratinocytes (vector controls) with those expressing recombinant plakophilin 1 introduced by retroviral transduction. We found that plakophilin 1 increases desmosomal protein content within the cell rather than enhancing transcriptional levels of desmosomal genes. Re-expression of plakophilin 1 in null cells retards cell migration but does not alter keratinocyte cell growth. Confluent sheets of plakophilin 1-deficient keratinocytes display fewer calcium-independent desmosomes than do plakophilin 1-deficient keratinocytes expressing recombinant plakophilin 1 or keratinocytes expressing endogenous plakophilin 1. In addition electron microscopy studies show that re-expression of plakophilin 1 affects desmosome size and number. Collectively, these results demonstrate that restoration of plakophilin 1 function in our culture system influences the transition of desmosomes from a calcium-dependent to a calcium-independent state and this correlates with altered keratinocyte migration in response to wounding. Thus, plakophilin 1 has a key role in increasing desmosomal protein content, in desmosome assembly, and in regulating cell migration.

3T3 Cells↗
PubMed2003

Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome.

Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed "KIND1" [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.

Abnormalities, Multiple↗
PubMed2003

Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation.

The autosomal recessive disorder lipoid proteinosis results from mutations in extracellular matrix protein 1 (ECM1), a glycoprotein expressed in several tissues (including skin) and composed of two alternatively spliced isoforms, ECM1a and ECM1b, the latter lacking exon 7 of this 10-exon gene (ECM1). To date, mutations that either affect ECM1a alone or perturb both ECM1 transcripts have been demonstrated in six cases. However, lipoid proteinosis is clinically heterogeneous with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurological abnormalities such as temporal lobe epilepsy. In this study, we sequenced ECM1 in 10 further unrelated patients with lipoid proteinosis to extend genotype-phenotype correlation and to add to the mutation database. We identified seven new homozygous nonsense or frameshift mutations: R53X (exon 3); 243delG (exon 4); 507delT (exon 6); 735delTG (exon 7); 785delA (exon 7); 892delC (exon 7) and 1190insC (exon 8), as well as two new compound heterozygous mutations: W160X/F167I (exon 6) and 542insAA/R243X (exons 6/7), none of which were found in controls. The mutation 507delT occurred in two unrelated subjects on different ECM1 haplotypes and may therefore represent a recurrent mutation in lipoid proteinosis. Taken with the previously documented mutations in ECM1, this study supports the view that exons 6 and 7 are the most common sites for ECM1 mutations in lipoid proteinosis. Clinically, it appears that mutations outside exon 7 are usually associated with a slightly more severe mucocutaneous lipoid proteinosis phenotype, but neurological features do not show any specific genotype-phenotype correlation.

Adolescent↗
PubMed2003

Alterations in desmosome size and number coincide with the loss of keratinocyte cohesion in skin with homozygous and heterozygous defects in the desmosomal protein plakophilin 1.

Recessive mutations in the desmosomal plaque protein plakophilin 1 (PkP1) underlie ectodermal dysplasia/skin fragility syndrome (MIM 604536). We undertook an immunohistochemical and quantitative electron microscopic examination of suprabasal desmosomes from 4 skin samples from 3 PkP1 deficient patients, an unaffected carrier with a PKP1 heterozygous acceptor splice site mutation and 5 healthy control subjects. Desmosomal plaque size (>50 desmosomes per individual) and frequency (>20 high power fields, HPF) were assessed. Compared with controls, desmosomes were reduced dramatically both in size (49%) and frequency (61%) in the lower suprabasal layers (LSB) in PkP1 null patients (P<0.01). In the LSB compartment of the heterozygous carrier, corresponding reductions were 37% and 20%, respectively (P<0.01). Surprisingly, the PkP1 null patient's upper suprabasal layer, (USB), desmosome size was larger (59%, P<0.01) than the control value, and showed increased desmoglein 1 and PkP2 USB staining. The USB desmosome frequency in PKP1 null patients was similar to the LSB compartment (but reduced by 43% compared to USB controls). The carrier showed no difference in the USB desmosome size and frequency compared with the controls (P>0.05). The PKP1 null patients showed poorly developed inner and outer desmosomal plaques. Thus, both the patients and unaffected carrier showed reductions in the LSB desmosome size and number; despite only PkP1 null patients exhibiting any phenotype. These findings attest to the molecular recruiting and stabilizing roles of PkP1 in desmosome formation, particularly in the LSB compartment.

Adolescent↗
PubMed2002

Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1).

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.

Blood Vessels↗
PubMed2002

Positional cloning identifies a novel cyclophilin as a candidate amplified oncogene in 1q21.

Gains of 1q21-q23 have been associated with metastasis and chemotherapy response, particularly in bladder cancer, hepatocellular carcinomas and sarcomas. By positional cloning of amplified genes by yeast artificial chromosome-mediated cDNA capture using magnetic beads, we have identified three candidate genes (COAS1, -2 and -3) in the amplified region in sarcomas. COAS1 and -2 showed higher amplification levels than COAS3. Most notably, amplification was very common in osteosarcomas, where in particular COAS2 was highly expressed. COAS1 has multiple repeats and shows no homology to previously described genes, whereas COAS2 is a novel member of the cyclosporin-binding peptidyl-prolyl isomerase family, very similar to cyclophilin A. COAS2 was overexpressed almost exclusively in aggressive metastatic or chemotherapy resistant tumours. Although COAS2 was generally more amplified than COAS1, it was not expressed in well-differentiated liposarcomas, where amplification of this region is very common. All three genes were found to be amplified and over-expressed also in breast carcinomas. The complex nature of the 1q21-23 amplicons and close proximity of the genes make unequivocal determination of the gene responsible difficult. Quite likely, the different genes may give selective advantages to different subsets of tumours.

Amino Acid Sequence↗
PubMed2002

Strategies to identify disease genes.

The correlation between genes and disease began in earnest in the early 1900s with the identification of Mendelian-like inheritance of "inborn errors of metabolism." Since then, the ever-broadening field of genetics has been established as one of the most important and groundbreaking branches of science and medicine to date. With the announcement of a "working draft" sequence of the human genome in 2001, the vast array of both genomic and expressed sequence information available in the public databases alone has meant that the concept of hunting for genes is evolving. Nowadays, researchers can substitute many labor-intensive hours in the lab for less time searching on the World Wide Web. Specialization within genetics has been continuously providing subsets of the genre such as genomics, pharmacogenetics, chemogenomics, gene therapy, proteomics and functional genomics, all of which are based on the fundamental starting block, the gene. This review aims to summarize both traditional and current strategies for identifying susceptibility and monogenetic disease genes and describes how these strategies have evolved in tune with the ever-expanding wealth of information now available at our fingertips.

Animals↗