• Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells.

      Breitwieser, Wolfgang; Lyons, Steve; Flenniken, Ann Marie; Ashton, Garry; Bruder, Gail; Willington, Mark; Lacaud, Georges; Kouskoff, Valerie; Jones, Nic; Cell Regulation Department, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom. (2007-08-15)
      The ATF2 transcription factor is phosphorylated by the stress-activated mitogen-activated protein kinases (MAPKs) JNK and p38. We show that this phosphorylation is essential for ATF2 function in vivo, since a mouse carrying mutations in the critical phosphorylation sites has a strong phenotype identical to that seen upon deletion of the DNA-binding domain. In addition, combining this mutant with a knockout of the ATF2 homolog, ATF7, results in embryonic lethality with severe abnormalities in the developing liver and heart. The mutant fetal liver is characterized by high levels of apoptosis in developing hepatocytes and haematopoietic cells. Furthermore, we observe a significant increase in active p38 due to loss of a negative feedback loop involving the ATF2-dependent transcriptional activation of MAPK phosphatases. In embryonic liver cells, this increase drives apoptosis, since it can be suppressed by chemical inhibition of p38. Our findings demonstrate the importance of finely regulating the activities of MAPKs during development.
    • Feedback regulators in normal and tumour tissues.

      Lord, Brian I; Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (1988)
      Regulation of cell behaviour and population size is presumed to be not unlike classical regulation in non-biological systems, i.e. it is controlled by the cybernetic principle of negative feedback whereby the performance of progenitor cells depends inversely on a signal from their product, the size of which is proportional to the mass of the product. This signal may be inhibitory, acting directly on the progenitor cells. Alternatively, it may operate via an indirect and integrated inhibitor/stimulator feedback loop in which the one influences the production of the other. Illustrations taken from the various phases of haemopoietic development show the operation of these loops. Haemopoietic stem cells are under the direct influence of both inhibitor and stimulator but it is a feedback signal from the stem cell population that dictates the production of the one rather than the other. A second inhibitor acting at the stem cell level is a low molecular weight tetrapeptide which blocks the entry of cells into DNA synthesis, thus protecting them during a regimen of treatment with an S-phase cytotoxic drug. Proliferation of the maturing cells is also inhibited by feedback products of their fully mature descendants. Here, the effect is one of cell cycle modulation, whereas in the stem cell population the inhibitor and stimulator effect an on/off switch. Attempts to characterize the molecules involved have been limited. A series of tri- to pentapeptides has been described for haemopoietic or epithelial cell inhibitors. A common feature of several is a pGlu-Glu end though whether this has any significance is not known. In tumours it has been shown that some ascites are self-limiting and treatment of small tumours with cell-free fluid from a mature growth blocks their further growth. It appears that many tumour cells produce the feedback signals characteristic of their normal counterparts but are themselves less sensitive to it. The same is true of transforming growth factor-beta which is produced and detected by virtually all cell types. In this case, the factor, inhibiting in most cases, is produced in inactive form and achieves its target specificity by a localized capacity to activate it. Some tumours, while responding to exogenous active TGF-beta are incapable of activating the latent molecule. It is concluded that the differential sensitivity of normal and neoplastic tissues to physiological feedback regulators is a potentially exploitable property in cancer therapy.
    • Fern spore extracts can damage DNA.

      Simán, S E; Povey, Andrew C; Ward, Timothy H; Margison, Geoffrey P; Sheffield, E; CRC Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (2000-07)
      The carcinogenicity of the vegetative tissues of bracken fern (Pteridium) has long been established. More recently, the carcinogenic effects of the spores of bracken have also been recognized. Both vegetative tissues and spores of bracken can induce adducts in DNA in animal tissues, but the possible genotoxic or carcinogenic effects of spores from fern species other than bracken are unknown. The single-cell gel electrophoresis ('comet') assay was used to investigate whether fern spores can cause DNA damage in vitro. Extracts of spores from six fern species were administered to cultured human premyeloid leukaemia (K562) cells. Spore extracts of five fern species: Anemia phyllitidis, Dicksonia antarctica, Pteridium aquilinum, Pteris vittata and Sadleria pallida, induced significantly more DNA strand breaks than those in the control groups. Only in one species, Osmunda regalis, was the effect no different from that in the control groups. Using extracts from A. phyllitidis and P. vittata, the extent of DNA damage was increased by increasing the original dose 10 times, whereas an experiment in which exposure times were varied suggested that the highest levels of strand breaks appear after 2 h exposure. Simultaneous incubation with human S9 liver enzyme mix ablated the damaging effect of the extracts. Our data show that fern spore extracts can cause DNA damage in human cells in vitro. Considering the strong correlation between DNA damage and carcinogenic events, the observations made in this report may well have some implications for human health.
    • Fibrillin-1 interactions with heparin. Implications for microfibril and elastic fiber assembly.

      Cain, Stuart A; Baldock, Clair; Gallagher, John T; Morgan, Amanda; Bax, Daniel V; Weiss, Anthony S; Shuttleworth, C Adrian; Kielty, Cay M; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom. (2005-08-26)
      Fibrillin-1 assembly into microfibrils and elastic fiber formation involves interactions with glycosaminoglycans. We have used BIAcore technology to investigate fibrillin-1 interactions with heparin and with heparin saccharides that are analogous to S-domains of heparan sulfate. We have identified four high affinity heparin-binding sites on fibrillin-1, localized three of these sites, and defined their binding kinetics. Heparin binding to the fibrillin-1 N terminus has particularly rapid kinetics. Hyaluronan and chondroitin sulfate did not interact significantly with fibrillin-1. Heparin saccharides with more than 12 monosaccharide units bound strongly to all four fibrillin-1 sites. Heparin did not inhibit fibrillin-1 N- and C-terminal interactions or RGD-dependent cell attachment, but heparin and MAGP-1 competed for binding to the fibrillin-1 N terminus, and heparin and tropoelastin competed for binding to a central fibrillin-1 sequence. By regulating these key interactions, heparin can profoundly influence microfibril and elastic fiber assembly.
    • Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer.

      Hessmann, E; Patzak, M S; Klein, L; Chen, N; Kari, V; Ramu, I; Bapiro, T E; Frese, Kristopher K; Gopinathan, A; Richards, F M; et al. (2017-01-10)
      Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery.
    • Fibroblast growth factor receptors (FGFRs) and noncanonical partners in cancer signaling

      Ferguson, H. R.; Smith, M. P; Francavilla, Chiara; Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, Manchester M13 9PT, (2021)
      Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration.
    • Fibroblast growth factor-2 binds to small heparin-derived oligosaccharides and stimulates a sustained phosphorylation of p42/44 mitogen-activated protein kinase and proliferation of rat mammary fibroblasts.

      Delehedde, Maryse; Lyon, Malcolm; Gallagher, John T; Rudland, Philip S; Fernig, David G; School of Biological Sciences, Life Science Building, University of Liverpool, Crown Street, Liverpool L69 7ZB, U.K. (2002-08-15)
      We examine the relationship between the chain length of heparin-derived oligosaccharides, fibroblast growth factor (FGF)-2 binding kinetics and the ability of the oligosaccharides to allow FGF-2-induced proliferation of chlorate-treated rat mammary fibroblasts. First, using an optical biosensor, we show that FGF-2 did not bind disaccharides, but definitively bound to tetrasaccharides. As the chain length increased from tetrasaccharide to octasaccharide, there was a substantial increase in k(ass) (564000 M(-1) x s(-1) to 2000000 M(-1) x s(-1), respectively) and affinity (K(d) 77 nM to 11 nM, respectively) for FGF-2. From decasaccharides and longer, the k(ass) and affinity for FGF-2 was reduced substantially (tetradecasaccharide k(ass) 470000 M(-1) x s(-1), K(d) 30 nM). In chlorate-treated, and hence sulphated, glycosaminoglycan-deficient cells, FGF-2 alone or in the presence of disaccharides did not stimulate DNA synthesis and it only elicited an early transient dual phosphorylation of p42/44 mitogen-activated protein kinase (MAPK). In the same cells FGF-2 in the presence of tetrasaccharides and longer oligosaccharides was able to restore DNA synthesis and enable the sustained dual phosphorylation of p42/44(MAPK). However, the oligosaccharides from tetrasaccharides to octasaccharides were less potent in proliferation assays than deca- and longer oligosaccharides. Therefore, there was no correlation between the binding parameters and the potency of the oligosaccharides in DNA synthesis assays. These results demonstrate that tetrasaccharides are able to bind FGF-2 and enable FGF-2 to stimulate cell proliferation, which sets important boundary conditions for models of the FGF-2-heparan sulphate-FGF receptor complex.
    • Fibroblast growth factor-2 stimulation of p42/44MAPK phosphorylation and IkappaB degradation is regulated by heparan sulfate/heparin in rat mammary fibroblasts.

      Delehedde, Maryse; Seve, Michel; Sergeant, Nicolas; Wartelle, Isabelle; Lyon, Malcolm; Rudland, Philip S; Fernig, David G; School of Biological Sciences, Life Sciences Building, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom. (2000-10-27)
      Fibroblast growth factor-2 (FGF-2) interacts with a dual receptor system consisting of tyrosine kinase receptors and heparan sulfate proteoglycans (HSPGs). In rat mammary fibroblasts, FGF-2 stimulated DNA synthesis and induced a sustained phosphorylation of p42/44(MAPK) and of its downstream target, p90(RSK). Moreover, FGF-2 also stimulated the transient degradation of IkappaBalpha and IkappaBbeta. PD098059, a specific inhibitor of p42/44(MAPK) phosphorylation, inhibited FGF-2-stimulated DNA synthesis, phosphorylation of p42/44(MAPK) and p90(RSK), and degradation of IkappaBbeta. In contrast, in chlorate-treated and hence sulfated glycosaminoglycan-deficient cells, FGF-2 was unable to stimulate DNA synthesis. However, FGF-2 was able to trigger a transient phosphorylation of both p42/44(MAPK) and p90(RSK), which peaked at 15 min and returned to control levels at 30 min. In these sulfated glycosaminoglycan-deficient cells, no degradation of IkappaBalpha and IkappaBbeta was observed after FGF-2 addition. However, in chlorate-treated cells, the addition of heparin or purified HSPGs simultaneously with FGF-2 restored DNA synthesis, the sustained phosphorylation of p42/44(MAPK) and p90(RSK), and the degradation of IkappaBalpha and IkappaBbeta. These results suggest that the HSPG receptor for FGF-2 not only influences the outcome of FGF-2 signaling, e.g. cell proliferation, but importantly regulates the immediate-early signals generated by this growth factor.
    • Fibroblasts from Li-Fraumeni patients are resistant to low dose-rate irradiation.

      Sproston, Anthony R; Boyle, John M; Heighway, Jim; Birch, Jillian M; Scott, David; CRC Department of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Manchester, UK. (1996-08)
      A group of adult skin fibroblast cultures from four individuals representing Li-Fraumeni families with different mutations in the p53 gene were found to be resistant to low dose-rate (0.011 Gy per min) 60Co radiation when compared with a control group of four cultures from normal individuals. The Li-Fraumeni fibroblasts, which could not be distinguished from controls after high dose rate (1.07 Gy per min) irradiation, were shown to be heterozygous (+/mut) at the p53 locus at the time of irradiation.
    • Fibronectin and the cytoskeleton of epithelial cells.

      Tolson, N; Hopkins, C; Sheterline, P; Schor, Seth L; Department of Histology and Cell Biology (Medical), The University, Liverpool, UK (1980)
    • FIGHT-302: Phase III study of first-line (1L) pemigatinib (PEM) versus gemcitabine (GEM) plus cisplatin (CIS) for cholangiocarcinoma (CCA) with FGFR2 fusions or rearrangements

      Bekaii-Saab, T. S.; Valle, Juan W; Van Cutsem, E.; Rimassa, L.; Furuse, J.; Ioka, T.; Melisi, D.; Macarulla, T.; Bridgewater, J. A.; Wasan, H. S.; et al. (2020)
      Background: For advanced CCA, standard of care 1L systemic treatment is GEM + CIS. Genetic alterations in intrahepatic CCA provide potential therapeutic targets. Fibroblast growth factor receptor (FGFR) 2 gene rearrangements driving CCA tumorigenesis were identified almost exclusively in intrahepatic CCA patients (pts) (incidence, 10?16%). In phase 2, PEM (INCB054828), a selective, potent, oral FGFR1?3 inhibitor elicited an objective response rate (ORR) of 35.5% and median progression-free survival (PFS) of 6.9 months (mo) in previously treated, locally advanced or metastatic CCA with FGFR2 rearrangements (NCT02924376). FIGHT-302, a randomized, open-label, phase 3 study will evaluate efficacy and safety of 1L PEM vs GEM + CIS in unresectable/metastatic CCA with FGFR2 fusions or rearrangements (NCT03656536). Methods: Eligible pts are adults with confirmed unresectable/metastatic CCA; no prior systemic therapy for advanced disease < 6 mo before enrollment; radiographically measurable/evaluable disease (per RECIST v1.1); ECOG PS ?1; documented FGFR2 fusions or rearrangements. Exclusions include clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification; untreated CNS metastases or history of uncontrolled seizures. Pts will be randomized (1:1; stratified by region and tumor burden) to PEM 13.5 mg QD on a 21-day (d) cycle or GEM (1000 mg/m2) + CIS (25 mg/m2) on D1 and D8 of 21-d cycles (max 8). Crossover to PEM allowed after confirmed progression. PEM titration to 18 mg from cycle 2 allowed for pts without hyperphosphatemia (serum phosphate > 5.5 mg/dL) and Grade ?2 treatment-related adverse events during cycle 1. Hyperphosphatemia will be managed with diet modifications, phosphate binders, diuretics, or dose adjustments. Treatment will continue until progression or unacceptable toxicity. Primary endpoint is PFS (by independent review). Secondary endpoints are ORR, overall survival, duration of response, disease control rate, safety, and quality of life. Four pts (target N = 432) are enrolled as of Sep 25, 2019. Clinical trial information: NCT03656536.
    • Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma.

      Gore, M; Szczylik, C; Porta, C; Bracarda, S; Bjarnason, G; Oudard, S; Lee, S; Haanen, J; Castellano, D; Vrdoljak, E; et al. (2015-06-30)
      We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials.
    • Final results of CA180-372/COG AALL1122 phase 2 trial of dasatinib and chemotherapy in pediatric patients with newly-diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (PH plus ALL)

      Hunger, S.; Saha, Vaskar; Devidas, M.; Valsecchi, M.; Gastier-Foster, J.; Cazzaniga, G.; Reshmi, S.; Borowitz, M.; Moorman, A.; Heerema, N.; et al. (2020)
      Background and Aims: We administered EsPhALL chemotherapy plus dasatinib 60 mg/m 2 (starting day 15) at COG (North America and Aus- tralia) and EsPhALL (Italy and UK) sites. Patients (>1-17.99 years) with MRD 0.05% following induction Ib or MRD-positive follow- ing three additional high-risk (HR) chemotherapy blocks were allo- cated to CR1 HSCT. The remaining patients received chemother- apy plus dasatinib for 2 years. Only CNS3 patients received cranial irradiation. Methods: Enrollment was 109 patients (3/2012-5/2014); 3 were ineli- gible and received no trial therapy. Results: All 106 treated-patients achieved CR. With database lock 6/29/19, 48/106 had events including 38 relapses (24 marrow, 4 CNS, 4 marrow+CNS, 4 other, 2 marrow+other), 9 treatment-related deaths (7 in chemotherapy-assigned patients, 2 post-HSCT), and one malignancy. Nineteen (17.9%) patients met HSCT criteria, 15 (14.2%) received CR1 HSCT with 9 remaining event-free, 2 transplant-related deaths (6 weeks, 7 months), and 4 relapses (3 alive, 1 died). Among the four not transplanted, 2 were event-free, 1 relapsed and died, and 1 had an astrocytoma. The remaining 87 patients were assigned to chemotherapy plus dasatinib, with 47 remaining event-free. Seven died in CR1, 5 on-therapy (3 in HR3, 1 reinduction 2, 1 continuation) and 2 post-therapy (21 and 31 months). Thirty-three relapsed, 3 on-therapy at 16-23 months (all alive) and 30 post-therapy (18 12 months, 12 >12 months; 22 alive and 8 deceased). The primary toxicities were febrile neutropenia and infection; one chemotherapy patient discon- tinued dasatinib (allergy) and one discontinued post-HSCT (myelosup- pression). Conclusions: Dasatinib plus EsPhALL chemotherapy is safe and effec- tive in pediatric Ph +ALL. With only 14% of patients undergoing CR1 HSCT, as compared to 81% in the EsPhALL 2004 and 38% in the EsPhALL2010 imatinib trials, this trial demonstrates similar outcomes with 5-year EFS 54.6% (95% CI, 44.5-63.6) and OS 81.7% (95% CI, 82.8-87.9) versus 60.3%/71.5% in EsPhALL 2004, and 57%/71.8% in EsPhALL 2010
    • The fine structure and cell kinetics of mouse epidermis after wounding.

      Potten, Christopher S; Allen, Terence D; Paterson Laboratories, CHristie Hospital and Holt Radium Institute, Manchester (1975-03)
      A variable amount of cornified tissue removed from mouse dorsal epidermis results in stimulation of the entire basal layer. Stimulation does not appear to be dependent on damage to an indiviaual epidermal proliferative unit (EPU). The immediate reaction to wounding is a rapid movement of cells from the basal layer to the differentiating compartment resulting in depopulation of the basal layer, which is followed by a burst in DNA-synthetic activity. The result of the increased transit of cells through the epidermis is that various aspects of keratinization can appear abnormal. The Langerhans cells show several changes, often appearing suprabasal and becoming smaller, rounded cells with a less-clear cytoplasm and fewer granules. The initial migratory reaction results in a largely normal epidermis on the third day. This reaction is followed by a transient hyperplasia which reaches its peak on the sixth to seventh day and gradually returns to normal by the fourteenth to fifteenth day. The hyperplasia is characterized by a loss of the ordered stacking of cornified cells which become shorter and thicker than normal. There is a return to the stacked state beginning on the tenth day. The Langerhans frequency is apparently at its lowest on days 6-7 when the proliferation levels are at their maximum. An inverse relationship appears to exist between relative Langerhans cell frequency and cell proliferation rate. The data suggest that the frequency of Langerhans granules also changes during the course of the hyperplasia, peak levels being observed just before the decline in proliferative activity.
    • Fine structure of heparan sulfate regulates syndecan-1 function and cell behavior.

      Sanderson, R D; Turnbull, Jeremy E; Gallagher, John T; Lander, A D; Department of Pathology, University of Arkansas for Medical Sciences, Little Rock 72205. (1994-05-06)
      Two myeloma cell lines, MPC-11 and P3X63Ag8.653 (P3), have almost identical amounts of syndecan-1 at their cell surface. The syndecan-1 molecules from both lines are similar in size, have indistinguishable core proteins, and have similarly sized heparan sulfate chains. Nevertheless, syndecan-1 on MPC-11 mediates cell adhesion to type I collagen, whereas P3 cells do not bind collagen. Affinity co-electrophoresis reveals that intact syndecan-1 isolated from P3 cells binds collagen poorly and that syndecan-1 heparan sulfate isolated from MPC-11 has a 20-fold higher affinity for collagen than syndecan-1 heparan sulfate from P3. Analysis of disaccharide composition and oligosaccharide mapping also reveals differences between MPC-11 and P3 heparan sulfate. Most notably, the level of N-sulfation and 2-O-sulfation is higher, and 6-O-sulfation lower, in syndecan-1 heparan sulfate from MPC-11 than from P3. Interestingly, levels of total sulfation of syndecan-1 heparan sulfate from MPC-11 and P3 are similar (75.6 and 72.6 sulfates/100 disaccharides, respectively), indicating that the difference in their affinity for collagen is not due to a difference in net charge. These data indicate that the fine structure of heparan sulfate can differ on identical proteoglycan core proteins, and these differences can control fundamental cellular properties such as cell-matrix adhesion.
    • Fine-structural aspects of bromodeoxyuridine incorporation in sister chromatid differentiation and replication banding.

      Jack, Elspeth M; Harrison, Christine J; White, Gavin R M; Ockey, Charles H; Allen, Terence D; Department of Ultrastructure, Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, UK. (1989-10)
      The structure of harlequin-stained chromosomes following substitution with low levels of 5-bromodeoxyuridine (BrdUrd) over two cell cycles and high levels over the last part of one cycle (replication banding) was studied in Chinese hamster ovary (CHO) cells. By using correlative light (LM) and scanning electron microscopy (SEM), it was shown that the effects of both the ultraviolet light (u.v.) and hot SSC treatment steps of the harlequin staining procedure were necessary to obtain sister-chromatid differentiation (SCD) or replication banding. u.v. treatment alone resulted in dark Giemsa staining of both chromatids with SEM morphology of short compact protuberances and an overall flattened smooth appearance in both the unsubstituted and BrdUrd-substituted chromatids, a morphology essentially similar to that of untreated chromosomes. SSC alone on the other hand resulted in dark-staining chromatids with an SEM morphology of raised, loosely packed loops of fibres in both types of chromatids. u.v. and SSC treatment together resulted in differentiation, with dark-staining unifilarly (TB) chromatids in the LM corresponding to raised loosely packed loops in the SEM and pale bifilarly (BB) chromatids corresponding to the smooth compact flattened SEM appearance. Where the BrdUrd-substituted strand became the template (BT), or when the nascent strand TB contained high levels of BrdUrd substitution in replication banding, the chromatid stained pale and showed the compact smooth appearance in the SEM. The Giemsa staining ability and ultrastructural morphology of harlequin staining is discussed with respect to putative DNA loss and also in terms of preferential protein-protein, protein-DNA cross-linkage in BrdUrd-containing DNA. These changes are also compared with the ultrastructural morphology observed after other banding methods, where deterioration of protein and DNA-protein interaction resulting in aggregation of chromatin fibres appears to be the major mechanism.
    • Fine-structural identification and organization of the epidermal proliferative unit.

      Allen, Terence D; Potten, Christopher S; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1974-07)
    • First in human phase 1/2a study of PEN-221 somatostatin analog (SSA)-DM1 conjugate for patients (PTS) with advanced neuroendocrine tumor (NET) or small cell lung cancer (SCLC): phase 1 results

      Halperin, DM; Johnson, ML; Meyer, T; Fojo, AT; Cook, Natalie; Blaszkowsky, LS; Schlechter, BL; Chan, J; Yao, JC; Jemiai, Y; et al. (2019)