An atypical presentation of renal mass associated with BAP-1 tumor predisposition syndrome: Case report and review of literature.

BCRA-associated protein-1 (BAP-1) mutation has been associated with the development of a familiar syndrome that predisposes to tumors with a higher incidence than in general population, including melanoma and renal carcinoma. We report a 47-year-old woman diagnosed with a BAPoma (melanocytic tumor characterized by the loss of BAP-1). Due to her extensive family history with multiple neoplasms, a FDG PET-CT was performed. Consequently, she was diagnosed with an atypical renal mass, which is rarely linked to this syndrome. We review and discuss the available literature on the screening, diagnosis and treatment of renal tumors associated with BAP-1 tumor predisposition syndrome.

Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.

Headache and pregnancy: a systematic review.

This systematic review summarizes the existing data on headache and pregnancy with a scope on clinical headache phenotypes, treatment of headaches in pregnancy and effects of headache medications on the child during pregnancy and breastfeeding, headache related complications, and diagnostics of headache in pregnancy. Headache during pregnancy can be both primary and secondary, and in the last case can be a symptom of a life-threatening condition. The most common secondary headaches are stroke, cerebral venous thrombosis, subarachnoid hemorrhage, pituitary tumor, choriocarcinoma, eclampsia, preeclampsia, idiopathic intracranial hypertension, and reversible cerebral vasoconstriction syndrome. Migraine is a risk factor for pregnancy complications, particularly vascular events. Data regarding other primary headache conditions are still scarce. Early diagnostics of the disease manifested by headache is important for mother and fetus life. It is especially important to identify "red flag symptoms" suggesting that headache is a symptom of a serious disease. In order to exclude a secondary headache additional studies can be necessary: electroencephalography, ultrasound of the vessels of the head and neck, brain MRI and MR angiography with contrast ophthalmoscopy and lumbar puncture. During pregnancy and breastfeeding the preferred therapeutic strategy for the treatment of primary headaches should always be a non-pharmacological one. Treatment should not be postponed as an undermanaged headache can lead to stress, sleep deprivation, depression and poor nutritional intake that in turn can have negative consequences for both mother and baby. Therefore, if non-pharmacological interventions seem inadequate, a well-considered choice should be made concerning the use of medication, taking into account all the benefits and possible risks.

A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is usually characterised by a progressive peripheral and autonomic neuropathy often with associated cardiac failure and is due to dominantly inherited transthyretin mutations causing accelerated amyloid deposition. The UK population is unique in that the majority of patients have the T60A missense mutation in ATTR where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland. The neuropathy phenotype is less well described than the cardiac manifestations in this group. METHODS: We present the findings from an observational cohort study of patients with ATTR attending the National Hospital Inherited Neuropathy Clinic between 2009 and 2013. Detailed clinical neurological and electrophysiological data were collected on all patients alongside correlating autonomic and cardiac assessments. Follow-up data were available on a subset. RESULTS: Forty-four patients with genetically confirmed ATTR were assessed; 37 were symptomatic; mean age at onset=62 years, range=38-75 years; 75.7% male. T60A was the most common mutation (17/37), followed by V30M (5/37). A severe, rapidly progressive, predominantly length dependent axonal sensorimotor neuropathy was the predominant phenotype. T60A patients were distinguished by earlier and more frequent association with carpal tunnel syndrome; a predominance of negative sensory symptoms at onset; significant vibration deficits; and a non-length dependent progression of motor deficit. Progression of the neuropathy was observed over a relatively short follow-up period (2 years) in 20 patients with evidence of clinically measurable annual change in Medical Research Council (MRC) sum score (-1.5 points per year) and Charcot Marie Tooth Neuropathy Score (CMTNS:2.7 points per year), and a congruent trend in the electrophysiological measures used. CONCLUSION: The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history.

Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy.

Hereditary transthyretin amyloidosis (ATTR) is a genetically and clinically heterogeneous disease manifesting with predominant peripheral and autonomic neuropathy; cardiomyopathy, or both. ATTR V122I is the most common variant associated with non-neuropathic familial amyloid cardiomyopathy. We present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment.

In vitro evaluation of TAT-OP1 osteogenic properties and prospects for in vivo applications.

So far, osteogenic protein 1 (OP1) is biotechnologically produced and approved for the treatment of human lumbar spine fusion and long bone non-union fractures. When combined with the TAT sequence, it has been demonstrated in vitro to be easily taken up by PC12 neuronal cells and to acquire its biological activity after intracellular refolding. In this study, TAT-OP1 was shown to be a useful strategy to efficiently drive denatured OP1 into mouse MC3T3E1 pre-osteoblasts. The correct in vitro protein refolding was verified by the activation of the BMP cascade, while the osteogenic potential of OP1 was demonstrated by increased expression of alkaline phosphatase, osteonectin and osteocalcin.

Recombinant human TAT-OP1 to enhance NGF neurogenic potential: preliminary studies on PC12 cells.

Osteogenic protein 1 (OP1), also known as bone morphogenic protein-7 (BMP7), is a multifunctional cytokine with demonstrated neurogenic potential. As the recombinant OP1 (rhOP1) was shown to provide axonal guidance cues and to prevent the reduction of dendritic growth in the injury-induced cortical cultures, it was suggested that an in vivo efficient rhOP1 delivery could enhance neurite growth and functional reconnectivity in the damaged brain. In the present work, we engineered a chimeric molecule in which rhBMP7 was fused to a protein transduction domain derived from HIV-1 TAT protein to deliver the denatured recombinant BMP7 into cells and obtain its chaperone-mediated folding, circumventing the expensive and not much efficient in vitro refolding procedures. When tested on rat PC12 cells, a widely used in vitro neurogenic differentiation model, the resulting fusion protein (rhTAT-OP1) demonstrated to enter fastly into the cells, lose HIV-TAT sequence and interact with membrane receptors activating BMP pathway by SMAD 1/5/8 phosphorylation. In comparison with nerve growth factor (NGF) and BMP7, it proved itself effective to induce the formation of more organized H and M neurofilaments. Moreover, if used in combination with NGF, it stimulated a significant (P < 0.05) and more precocious dendritic outgrowth with respect to NGF alone. These results indicate that rhTAT-OP1 fused with TAT transduction domain shows neurogenic activity and may be a promising enhancer factor in NGF-based therapies.

Effects of systemic administration of ciliary neurotrophic factor on Bax and Bcl-2 proteins in the lumbar spinal cord of neonatal rats after sciatic nerve transection.

Ciliary neurotrophic factor (CNTF) is a cytokine that plays a neuroprotective role in relation to axotomized motoneurons. We determined the effect of daily subcutaneous doses of CNTF (1.2 microg/g for 5 days; N = 13) or PBS (N = 13) on the levels of mRNA for Bcl-2 and Bax, as well as the expression and inter-association of Bcl-2 and Bax proteins, and the survival of motoneurons in the spinal cord lumbar enlargement of 2-day-old Wistar rats after sciatic nerve transection. Five days after transection, the effects were evaluated on histological and molecular levels using Nissl staining, immunoprecipitation, Western blot analysis, and reverse transcriptase-polymerase chain reaction. The motoneuron survival ratio, defined as the ratio between the number of motoneurons counted on the lesioned side vs those on the unlesioned side, was calculated. This ratio was 0.77 +/- 0.02 for CNTF-treated rats vs 0.53 +/- 0.02 for the PBS-treated controls (P < 0.001). Treatment with CNTF modified the level of mRNA, with the expression of Bax RNA decreasing 18% (with a consequent decrease in the level of Bax protein), while the expression of Bcl-2 RNA was increased 87%, although the level of Bcl-2 protein was unchanged. The amount of Bcl-2/Bax heterodimer increased 91% over that found in the PBS-treated controls. These data show, for the first time, that the neuroprotective effect of CNTF on neonatal rat axotomized motoneurons is associated with a reduction in free Bax, due to the inhibition of Bax expression, as well as increased Bcl-2/Bax heterodimerization. Thus, the neuroprotective action of the CNTF on axotomized motoneurons can be related to the inhibition of this apoptotic pathway.

Effects of systemic administration of ciliary neurotrophic factor on Bax and Bcl-2 proteins in the lumbar spinal cord of neonatal rats after sciatic nerve transection

Ciliary neurotrophic factor (CNTF) is a cytokine that plays a neuroprotective role in relation to axotomized motoneurons. We determined the effect of daily subcutaneous doses of CNTF (1.2 µg/g for 5 days; N = 13) or PBS (N = 13) on the levels of mRNA for Bcl-2 and Bax, as well as the expression and inter-association of Bcl-2 and Bax proteins, and the survival of motoneurons in the spinal cord lumbar enlargement of 2-day-old Wistar rats after sciatic nerve transection. Five days after transection, the effects were evaluated on histological and molecular levels using Nissl staining, immunoprecipitation, Western blot analysis, and reverse transcriptase-polymerase chain reaction. The motoneuron survival ratio, defined as the ratio between the number of motoneurons counted on the lesioned side vs those on the unlesioned side, was calculated. This ratio was 0.77 ± 0.02 for CNTF-treated rats vs 0.53 ± 0.02 for the PBS-treated controls (P < 0.001). Treatment with CNTF modified the level of mRNA, with the expression of Bax RNA decreasing 18 percent (with a consequent decrease in the level of Bax protein), while the expression of Bcl-2 RNA was increased 87 percent, although the level of Bcl-2 protein was unchanged. The amount of Bcl-2/Bax heterodimer increased 91 percent over that found in the PBS-treated controls. These data show, for the first time, that the neuroprotective effect of CNTF on neonatal rat axotomized motoneurons is associated with a reduction in free Bax, due to the inhibition of Bax expression, as well as increased Bcl-2/Bax heterodimerization. Thus, the neuroprotective action of the CNTF on axotomized motoneurons can be related to the inhibition of this apoptotic pathway.

Evidence for FSH-dependent upregulation of SPATA2 (spermatogenesis-associated protein 2).

Here we report the cloning and characterization of a novel cDNA named spata 2. SPATA2 is the ortholog of PD1, a human testicular protein which has been suggested to play a role in spermatogenesis. The spata 2 sequence reveals an open reading frame encoding a protein of 511 amino acids. Northern blot analysis with rat mRNA demonstrated two distinct transcripts of 2.2 and 4.0 kb. Tagging recombinant SPATA2 with the green fluorescent protein (GFP) and expressing the chimeric polypeptide in HLtat transfected cells indicated that SPATA2 is located in the nucleus. RT-PCR analysis revealed that spata 2 mRNA is expressed in the testis and to a lesser extent in the brain while skeletal muscle and kidney showed a barely visible signal. The same analysis demonstrated that isolated Sertoli cells express spata 2 mRNA. Treating Sertoli cells with FSH in vitro induced remarkable changes in the steady-state level of spata 2 mRNA in a time-dependent manner. In developing testis spata 2 transcripts were first detected 10 days post partum and expression levels increased steadily with age. The ability of FSH to stimulate spata 2 mRNA expression as well as its developmental expression suggests that this protein might play a role in regulating spermatogenesis and thus, according to the Gene Nomenclature Committee, we propose the name SPATA2 (Spermatogenesis associated protein 2) for this protein (or gene).

Bovine prion protein as a modulator of protein kinase CK2.

On the basis of far-Western blot and plasmon resonance (BIAcore) experiments, we show here that recombinant bovine prion protein (bPrP) (25-242) strongly interacts with the catalytic alpha/alpha' subunits of protein kinase CK2 (also termed 'casein kinase 2'). This association leads to increased phosphotransferase activity of CK2alpha, tested on calmodulin or specific peptides as substrate. We also show that bPrP counteracts the inhibition of calmodulin phosphorylation promoted by the regulatory beta subunits of CK2. A truncated form of bPrP encompassing the C-terminal domain (residues 105-242) interacts with CK2 but does not affect its catalytic activity. The opposite is found with the N-terminal fragment of bPrP (residues 25-116), although the stimulation of catalysis is less efficient than with full-size bPrP. These results disclose the potential of the PrP to modulate the activity of CK2, a pleiotropic protein kinase that is particularly abundant in the brain.

The immunosuppressant steroid cholesterylphosphoserine inhibits tumour necrosis factor-alpha secretion in vitro and in vivo.

The synthetic steroid cholesterylphosphoserine (CPHS) inhibited the secretion of TNF-alpha in lipopolysaccharide-challenged human monocytes. CPHS (5-20 microM) was effective when added together with the endotoxin, or after an interval (1-2 h) sufficient to have allowed for initiation of TNF-alpha synthesis. Consistently, CPHS did not alter TNF-alpha gene transcription. In contrast to its action on TNF-alpha, CPHS showed only marginal effects on interleukin 1beta secretion. Given intraperitoneally to mice 2 h before lipopolysaccharide CPHS prevented the rise in plasma TNF-alpha (IC(50): 5 mg/kg). The inhibition of TNF-alpha secretion by CPHS may contribute to the immunosuppressive activity of this steroid.

Increased plasma levels of platelet-derived growth factor (PDGF-BB + PDGF-AB) in patients with never-treated mild essential hypertension.

Platelet-derived growth factor (PDGF) could play a role in both vascular hypertrophy and atherosclerotic disease associated with hypertension. To assess whether plasma PDGF level is increased in mild essential hypertension, we measured plasma PDGF concentration in 25 never-treated patients with uncomplicated mild essential hypertension and in 22 normotensive healthy subjects. To evaluate the contribution of platelets to plasma PDGF in the two groups, we also measured plasma beta-thromboglobulin (BTG). Measurement of PDGF was carried out through an enzyme-linked immunoadsorbent assay, which detects two PDGF dimers, namely PDGF-BB and PDGF-AB. Both plasma PDGF and BTG were higher in the hypertensive than in the normotensive subjects. The ratio of PDGF to BTG was similar in the two groups. Plasma PDGF was weakly correlated with plasma BTG in the normotensive subjects, whereas this relationship was lost in the hypertensive patients. Our results suggest that the increase in plasma PDGF (PDGF-AB + PDGF-BB) in never-treated essential hypertension is mainly due to platelet activation. The increased circulating level of PDGF could play a role in the vascular structural changes associated with hypertension.

Expression study on D123 gene product: evidence for high positivity in testis.

A novel 44-kDa gene product (D123) has been proposed as necessary for S-phase entry of the cell cycle: a point mutation resulted in a temperature-sensitive arrest in G1-phase. From human fibrosarcoma cDNA library, we have isolated an identical gene and studied its sequence and mRNA and protein expression. Compared with D123, three nucleotide differences within the human coding sequence, plus others, result in a change of two amino acids. A partial sequence similarity has been found with a yeast gene of unknown function. The protein has several potential phosphorylation sites, is highly hydrophilic, and may be highly structured in alpha-helix. The mRNA is abundantly expressed by a variety of normal and transformed cells and by all tissues examined, being most highly expressed in testis. Specific antibodies, raised against a rhD123 polypeptide, recognize a major 42- to 44-kDa molecule in crude extract of various human cell lines. Immunohistochemistry reveals that D123 protein is not homogeneously expressed: it is detected, often in granular vescicles, in the cytoplasm of some epithelial, stromal, and sperm cells and in varicosities lining nervous fibers, while it appears to be absent in nuclei, endothelial, and smooth muscle cells. The precise link between cytoplasmic occurrence of D123 and cell cycle progression still remains to be clarified.

CNTF up-regulation of TIMP-2 in neuroblastoma cells.

The ciliary neurotrophic factor (CNTF) can regulate survival and differentiation of many types of developing and adult neurons; in metastatic SK-N-BE neuroblastoma cells, it promotes differentiation and neurite outgrowth. The expression of Gelatinase A (MMP-2) and its specific tissue inhibitor (TIMP-2), a degradative system whose balance is involved in matrix invasion and metastasis, was investigated in SK-N-BE cells cultured with and without CNTF or NGF. Zymographic analysis of conditioned media revealed that the cells constitutively secrete two gelatinases, mainly pro-MMP-2 but also traces of pro-MMP-9. In a time-course experiment in the presence of 25 ng/ml of CNTF, the MMP-2 mRNA expression showed no significant modulation, while TIMP-2 mRNA up-regulated to > 2-fold after 48 h and then fell dramatically. At the same concentrations, NGF showed no effect. TIMP-2 mRNA expression showed a dose-dependent increase of up to 8-fold from 1 to 250 ng/ml of CNTF and increased secretion of TIMP-2 was confirmed by Western blotting. MMP-2 was only slightly over-expressed under the same conditions, at either mRNA or protein level, with no correlation with neurocytokine concentration. These results suggest that boosting the expression of TIMP-2 by CNTF could restrain both matrix degradation following nervous system injury and neuroblastoma aggressiveness.

Recombinant human TIMP-3 from Escherichia coli: synthesis, refolding, physico-chemical and functional insights.

Matrix metalloproteinases are inhibited by a growing family of specific tissue inhibitors, TIMPs. The cDNA of the third member of the family, TIMP-3, was obtained by using a reverse transcription-polymerase chain reaction (RT-PCR) to amplify the corresponding mRNA from human placenta. Cloning and expression of the TIMP-3 were performed in Escherichia coli as a fusion protein with a 36 amino acid N-tail containing a His cluster. In the host vector system, rhTIMP-3 was stored intracellularly in its denatured, insoluble form in inclusion bodies. Slow dilution of denaturing and reducing agents, from rhTIMP-3 His bound to a metal affinity solid phase, was followed by partial acid removal of the N-tail, which leaves a residue of four amino acids. Circular dichroism, fluorescence and second-derivative UV spectroscopic analyses supported correct refolding of the recombinant and zymography showed inhibition of both MMP-2 and MMP-9 gelatinolytic activities. The role of the C-terminus, which has closer homology with TIMP-2 than TIMP-1, was also investigated: a C-truncated mutant, similarly cloned and expressed in E. coli, shows complete lack of inhibitory activity on MMP-9, still retaining some on MMP-2. The described protein engineering shows high yield of active inhibitor, unglycosylated as in the native form.

Synthesis and cytotoxic profile of a diphtheria toxin-neurotrophin-4 chimera.

A diphtheria toxin-neurotrophin-4/5 (NT-4/5) chimera (DAB389-NT4), in which the native receptor binding domain of diphtheria toxin was replaced with a synthetic gene encoding rat NT-4/5, was expressed, refolded, and purified. This fusion toxin has a deduced molecular mass of 60,163 and is formed by joining the first 389 amino acids of diptheria toxin to amino acids 1-130 of mature rat NT-4/5, using an NH2-terminal bridge of 33 additional amino acids including six consecutive histidines. Neural cell types expressing only p75LNGFR or p75LNGFR and full-length or truncated TrkB were used to evaluate the cytotoxic efficacy of DAB389-NT4. The fusion toxin produced a concentration-dependent killing of all cell populations, with LC50 values that largely reflected the known NT-4/5 binding affinities for these receptor proteins. Mean LC50 values ranged from 2,960 pM in p75LNGFR-expressing neuro-2a neuroblastoma cells to 1,075 and 70 pM, respectively, in hippocampal astrocytes (p75LNGFR+/truncated TrkB+) and cerebellar granule cells (p75LNGFR+/TrkB+). The LC50 for DAB389-NT4 in receptor-negative 3T3 fibroblasts was 20 nM. NT-4/5 and brain-derived neurotrophic factor but not ciliary neurotrophic factor added in excess neutralized DAB389-NT4 cytotoxicity. NT-4/5, however, did not reduce the cytotoxicity of intact diphtheria toxin.

Synthesis, cytotoxic properties and effects on early and late gene induction of a chimeric diphtheria toxin-leukemia-inhibitory factor protein.

Leukemia-inhibitory factor (LIF) is a neuropoietin able to regulate the differentiation and the survival of many cell types, which include some neuronal populations. The present study describes the genetic construction, expression, purification and properties of a diphtheria-toxin-related LIF gene fusion in which the native receptor-binding domain of diphtheria toxin was replaced with a gene encoding human LIF. The fusion protein expressed from the chimeric tox gene was designated DT-(1-389)-LIF-(2-184)-peptide. This fusion protein has a deduced molecular mass of 65980 Da and is formed by fusion of the first 389 amino acids of diphtheria toxin to amino acids 2-184 of mature human LIF, using a linker of 34 amino acids that includes six consecutive histidine residues. The latter span allows for single-step purification of the fusion protein by Ni(2+)-resin affinity chromatography. This linker provides a high degree of flexibility between the diphtheria toxin and LIF domains, thereby permitting aggregation-free refolding of the chimeric protein while bound to the affinity column. Both LIF and DT-(1-389)-LIF-(2-184)-peptide induced the phosphorylation of CLIP1 and CLIP2 in LIF-responsive neuroblastoma SH-N-BE cells. DT-(1-389)-LIF-(2-184)-peptide was selectively cytotoxic for cultured neuroblastoma cells bearing the LIF receptor, and for sympathetic neurons. The cytotoxic action of DT-(1-389)-LIF-(2-184)-peptide, like that of native diphtheria toxin, required receptor-mediated endocytosis, passage through an acidic compartment, and delivery of an ADP-ribosyltransferase to the cytosol of target cells. The latter point was confirmed by the fact that, while both LIF and DT-(1-389)-LIF-(2-184)-peptide increased c-fos mRNA expression in SH-N-BE cells, only LIF induced proenkephalin and c-fos promoter activities in cells transiently transfected with c-fos-chloramphenicol acetyltransferase and proenkephalin-chloramphenicol acetyltransferase fusion genes. Mutational analysis suggested that the C-terminal helix (helix D) of human LIF may, in part, constitute or contribute to the active site for LIF receptor binding and cell activation. The cytotoxic properties of DT-(1-389)-LIF-(2-184)-peptide may be useful in selectively depleting neuronal and immune cell populations that express the LIF beta receptor.