Parathyroid Hormone-related Peptide Levels Research Articles

Association between parathyroid hormone-related peptide levels and mortality in patients with malignancy

ObjectiveHypercalcemia of malignancy is a risk factor for mortality in patients with malignancies. Although the parathyroid hormone-related protein (PTHrP) secreted by tumor cells induces hypercalcemia, the association between serum PTHrP levels and mortality remains unclear. This study aimed to investigate the association between serum PTHrP levels and mortality in patients with malignancies. MethodsWe included patients with hypercalcemia (>10 mg/dL) and elevated PTHrP levels (>1.0 pmol/L) and analyzed mortality (overall survival after cancer diagnosis, PTHrP measurement, and 5-year survival rate). Moreover, using Cox proportional hazard model analysis, we investigated the impact of PTHrP levels on survival prognosis, assessing whether this effect varied depending on calcium concentration. ResultsWe analyzed the data of 183 patients. The median PTHrP level, corrected calcium level, and age were 5.5 (3.0–10.6) pmol/L, 12.5 (11.5–13.4) mg/dl, and 70 (61–76) years, respectively. PTHrP was significantly and linearly associated with serum calcium levels (correlation coefficient, 0.06; 95% confidence interval: 0.039–0.081, t: 5.69; p<0.001). The group with the highest PTHrP levels had significantly worse survival rates than the group with the lowest PTHrP levels (hazard ratio: 1.68, 95% confidence interval 1.03–2.77, p=0.038). ConclusionThis study showed an association between PTHrP and mortality in patients with malignancy after adjusting for serum calcium levels.

Immunoarray Measurements of Parathyroid Hormone-Related Peptides Combined with Other Biomarkers to Diagnose Aggressive Prostate Cancer.

Parathyroid hormone-related peptide (PTHrP) is related to bone metastasis and hypercalcemia in prostate and breast cancers and should be an excellent biomarker for aggressive forms of these cancers. Current clinical detection protocols for PTHrP are immunoradiometric assay and radioimmunoassay but are not sensitive enough to detect PTHrPs at early stages. We recently evaluated a prostate cancer biomarker panel, including serum monocyte differentiation antigen (CD-14), ETS-related gene protein, pigment epithelial-derived factor, and insulin-like growth factor-1, with promise for identifying aggressive prostate cancers. This panel predicted the need for patient biopsy better than PSA alone. In the present paper, we report an ultrasensitive microfluidic assay for PTHrPs and evaluate their diagnostic value and the value of including them with our prior biomarker panel to diagnose aggressive forms of prostate cancer. The immunoarray features screen-printed carbon sensor electrodes coated with 5 nm glutathione gold nanoparticles with capture antibodies attached. PTHrPs are bound to a secondary antibody attached to a polyhorseradish peroxidase label and delivered to the sensors to provide high sensitivity when activated by H2O2 and a mediator. We obtained an unprecedented 0.3 fg mL-1 limit of detection for PTHrP bioactive moieties PTHrP 1-173 and PTHrP 1-86. We also report the first study of PTHrPs in a large serum pool to identify aggressive malignancies. In assays of 130 human patient serum samples, PTHrP levels distinguished between aggressive and indolent prostate cancers with 83-91% clinical sensitivity and 78-96% specificity. Logistic regression identified the best predictive model as a combination of PTHrP 1-86 and vascular endothelial growth factor-D. PTHrP 1-173 alone also showed a high ability to differentiate aggressive and indolent cancers.

Significance of cancer stroma for bone destruction in oral squamous cell carcinoma using different cancer stroma subtypes.

Stromal cells in the tumor microenvironment (TME) can regulate the progression of numerous types of cancer; however, the bone invasion of oral squamous cell carcinoma (OSCC) has been poorly investigated. In the present study, the effect of verrucous SCC-associated stromal cells (VSCC-SCs), SCC-associated stromal cells (SCC-SCs) and human dermal fibroblasts on bone resorption and the activation of HSC-3 osteoclasts in vivo were examined by hematoxylin and eosin, AE1/3 (pan-cytokeratin) and tartrate-resistant acid phosphatase staining. In addition, the expression levels of matrix metalloproteinase (MMP)9, membrane-type 1 MMP (MT1-MMP), Snail, receptor activator of NF-κB ligand (RANKL) and parathyroid hormone-related peptide (PTHrP) in the bone invasion regions of HSC-3 cells were examined by immunohistochemistry. The results suggested that both SCC-SCs and VSCC-SCs promoted bone resorption, the activation of osteoclasts, and the expression levels of MMP9, MT1-MMP, Snail, RANKL and PTHrP. However, SCC-SCs had a more prominent effect compared with VSCC-SCs. Finally, microarray data were used to predict potential genes underlying the differential effects of VSCC-SCs and SCC-SCs on bone invasion in OSCC. The results revealed that IL1B, ICAM1, FOS, CXCL12, INS and NGF may underlie these differential effects. In conclusion, both VSCC-SCs and SCC-SCs may promote bone invasion in OSCC by enhancing the expression levels of RANKL in cancer and stromal cells mediated by PTHrP; however, SCC-SCs had a more prominent effect. These findings may represent a potential regulatory mechanism underlying the bone invasion of OSCC.

Prednisone-Responsive Hypercalcemia in a Patient With IgG4 Disease and Elevated Serum PTHrP Levels

Background: Ninety percent of hypercalcemia cases are related to either primary hyperparathyroidism or malignancy (1). This case presents one of the atypical etiologies of hypercalcemia. Clinical Case: A 53-year-old man with past medical history of nephrectomy was admitted for acute respiratory distress syndrome secondary to SARS-CoV-2. Hospital stay was complicated by septic shock and acute kidney injury requiring hemodialysis. Three months post hospital admission, the patient developed non-parathyroid (PTH) mediated hypercalcemia. Lab work results showed elevated serum calcium of 12.7 mg/dl (8.6–10.6), ionized calcium 6.8 mg/dl (4.2–5.4), albumin 2.6 g/dl (3.4–5.4), serum creatinine of 3.5 mg/dl (0.5–1.5), eGFR of 18.4 ml/min, and a PTH of 4 pg/ml (12–88). Liver profile - total bilirubin of 10.5 mg/dl (0–1.2), direct bilirubin of 5.9 mg/dl (0–0.2), GGTP 2055 U/L (6–60), alkaline phosphatase of 936 u/L (40–125), bone fractionated alkaline phosphatase 216 u/L (0–55), 25-OH Vitamin D of 11 ng/nl (20–80), 1,25 OH vitamin D of <5 pg/ml (19–79), TSH of 3.56 mciu/mL (0.35–4.0), CPK of 20 u/L (21–232) and a normal SPEP and immune-electrophoresisTreatment for hypercalcemia was initiated with calcitonin and oral steroids (prednisone 40mg/day for 4 days, 20mg/day for 1 day, and 10mg/day for 2 days), resulting in normalization of serum calcium. Patient received tube feedings that contained 2192 mcg retinol activity equivalents of vitamin A daily, which is associated with vitamin A intoxication in the presence of renal insufficiency. Vitamin A returned 0.78 mg/L (0.3–1.2). Serum Parathyroid hormone-related peptide (PTHrP) was elevated at 12.4 pmol/L (0.0–2.0). There was no obvious malignancy on various imaging studies. A magnetic resonance cholangiopancreatography (MRCP) showed biliary stricturing suggestive of primary sclerosing cholangitis (PSC), however, liver biopsy was not consistent with PSC. Serum IgG4 level was found to be elevated to 142 mg/dl (range: 1–123) which raised suspicion for autoimmune cholangiopathy. Discussion: Patient presented with non-PTH mediated hypercalcemia with low serum 1,25 OHD levels and elevated serum PTHrP level. Although most cases of elevated PTHrP associated with hypercalcemia are due to solid tumors, increased PTHrP levels have been seen in hypercalcemic patients with hematological malignancies and rare benign causes such as pneumonia (5). Association of elevated hypercalcemia with elevated IgG4 levels and PTHrP levels has not been previously reported. MRCP findings and abnormal morphology detailed in liver biopsy are suggestive of IgG4-related disease (IgG4RD) (3). The responsiveness in hypercalcemia to prednisone also supports this diagnosis. IgG4RD is associated with multi-organ autoimmune involvement. This case report highlights another complication of IgG4RD (i.e. hypercalcemia) associated with elevated PTHrP levels.

Hypercalcemia: A Metabolic Complication of an AIDS-Defining Illness

Abstract Background: Hypercalcemia may result from the activation of macrophages in granulomatous diseases with increased production of 1,25 dihydroxyvitamin D/calcitriol. Its occurrence in patients with human immunodeficiency virus-1 (HIV-1) infection may be atypical and signal major changes in immune status. We report on a patient with acquired immunodeficiency syndrome (AIDS) presenting with new-onset hypercalcemia after months of treatment for mycobacterium avium complex (MAC) infection and normal calcitriol levels. Clinical Case: A 37-year-old man on treatment for HIV-1 and disseminated MAC infection presented to the hospital 6 months after initial diagnosis with worsening headache, cough, and abdominal pain. On arrival he was afebrile and without palpable lymphadenopathy. He was found to have a high serum calcium (13.4 mg/dL, n 8.6–10.6 mg/dL) and acute kidney injury (AKI) (creatinine 4 mg/dL, n 0.6–1.25 mg/dL). His CD4 count had increased from 24 at time of diagnosis to 162 cells/μL (n 410–1,590 cells/μL); his HIV viral load was undetectable. Workup for hypercalcemia revealed an elevated phosphorus (5.2 mg/dL, n 2.5–5.0 mg/dL), low 25-OH vitamin D level (&amp;lt;13 ng/mL, n 25–80 ng/dL), low PTH (4.8 pg/mL, n 12–88 pg/mL), and calcitriol level of 31.4 pg/mL, n 19.9–73.3 pg/mL). Additional tests, including serum electrophoresis, thyroid stimulating hormone, and parathyroid hormone-related peptide levels, were unremarkable. The patient was diagnosed with hypercalcemia secondary to dysregulated calcitriol production in the setting of disseminated MAC and possible immune reconstitution. Hypercalcemia resolved with hydration and prednisone 20 mg daily. Patient was discharged with an 8-day prednisone taper, but readmitted to the hospital 3 weeks later with recurrent hypercalcemia (13.8 mg/dL) and AKI. Urine calcium was found to be elevated (484 mg/24 hours, n100-300 mg/24 hours) and repeat calcitriol was 53.6 pg/ml. Patient was restarted on prednisone 40 mg daily with normalization of calcium within 5 days (calcium 10.3 mg/dL). Conclusion: Hypercalcemia due to increased calcitriol production in the setting of MAC infection, an AIDS-defining illness, may occur months after initiation of effective antibiotic and antiviral therapy and could represent a manifestation of immune reconstitution. The deleterious effects of excess calcitriol may be present even in patients with chronic vitamin D deficiency and a calcitriol level that inappropriately remains within the normal range.

WITHDRAWN: HYPERCALCEMIA OF MALIGNANCY: SIMULTANEOUS ELEVATION OF PARATHYROID HORMONE-RELATED PEPTIDE AND 1,25 DIHYDROXYVITAMIN D IN SARCOMA

Abstract Objective Hypercalcemia is a common finding in patients who have an underlying malignancy. Only a few cases of hypercalcemia of malignancy have been linked to more than one mechanism of hypercalcemia. Here, we present a patient with liposarcoma and hypercalcemia of malignancy in the setting of simultaneous elevations in parathyroid hormone-related peptide (PTHrP) and 1,25 dihydroxyvitamin D [1,25(OH)2D] levels. Sarcoma-associated hypercalcemia is a rare disorder. Methods The patient was an 89-year-old woman with sarcoma-associated hypercalcemia. Multiple mechanisms were uncovered, and treatments were adjusted for them. Literature search for hypercalcemia of malignancy with multiple mechanisms was conducted. Results This is the first report describing dual mechanisms of sarcoma-associated hypercalcemia and only the fifth report on PTHrP and 1,25(OH)2D simultaneously causing hypercalcemia of malignancy. Conclusion Based on this finding, we recommend measuring the 1,25(OH)2D levels in conjunction with the PTHrP level in patients with malignancy as this would allow for a more proactive approach to the diagnosis and treatment of hypercalcemia of malignancy.

Transiently elevated parathyroid hormone-related peptide level associated with hypercalcemia and worsening renal insufficiency

Transiently elevated parathyroid hormone-related peptide level associated with hypercalcemia and worsening renal insufficiency

Effects of Serum Albumin, Calcium Levels, Cancer Stage and Performance Status on Weight Loss in Parathyroid Hormone-Related Peptide Positive or Negative Patients with Cancer.

BackgroundA recent animal study showed that parathyroid hormone-related peptide (PTHrP) is associated with cancer cachexia by promoting adipose tissue browning, and we previously demonstrated that PTHrP predicts weight loss (WL) in patients with cancer. In this study, we investigated whether prediction of WL by PTHrP is influenced by clinical factors such as serum albumin, corrected calcium levels, cancer stage, and performance status (PS).MethodsA cohort of 219 patients with cancer whose PTHrP level was measured was enrolled and followed for body weight (BW) changes. Subjects were divided into two groups by serum albumin (cutoff value, 3.7 g/dL), corrected calcium (cutoff value, 10.5 mg/dL), cancer stage (stage 1 to 3 or 4), or PS (Eastern Cooperative Oncology Group 0 to 1 or 2 to 4), respectively. Clinically significant WL was defined as either percent of BW change (% BW) <−5% or % BW <−2% plus body mass index (BMI) <20 kg/m2.ResultsAfter a median follow-up of 327 days, 74 patients (33.8%) experienced clinically significant WL. A positive PTHrP level was associated with a 2-fold increased risk of WL after adjusting for age, baseline BMI, serum albumin, corrected calcium level, cancer stage, and PS. The effect of PTHrP on WL remained significant in patients with low serum albumin, stage 4 cancer, and good PS. Regardless of calcium level, the effect of PTHrP on WL was maintained, although there was an additive effect of higher calcium and PTHrP levels.ConclusionEarly recognition of patients with advanced cancer who are PTHrP positive with hypercalcemia or hypoalbuminemia is needed for their clinical management.

PTHrP-related Hypercalcaemia in Infancy and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).

BackgroundSevere hypercalcaemia is a rare but clinically significant condition in infancy and childhood. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcaemia resulting from a malignancy is rare and only a handful of case reports have outlined its incidence alongside a benign condition.ObjectivesTo describe the diagnostic workup and management of an infant with hypercalcaemia, renal dysplasia, and elevated PTHrP levels.DesignCase report.SettingThe Victoria Hospital campus of the London Health Sciences Centre in London, Ontario, Canada.PatientsA child with congenital anomalies of the kidneys and urinary tract (CAKUT), stage 2 chronic kidney disease (CKD), and renal dysplasia who presented with severe hypercalcaemia.MeasurementsWeight, renal ultrasound, creatinine, cystatin C, eGFR, calcium, urea, bicarbonate, serum sodium, fractional sodium excretion, urine calcium to creatinine ratio, PTH, TSH, Free T4, AM cortisol, HMA, VMA, 25-vitamin D, 1,25 dihydroxy-vitamin D, calcitriol, vitamin A, ACE levels, skull and chest x-rays, alkaline phosphatase, CBC, tumour lysis profile, catecholamine breakdown, whole-body MRI, PTHrP.MethodsFull diagnostic workup and patient management. Patient treated with intravenous hydration, furosemide, calcitonin and CalciLo.ResultsPTHrP was elevated and no evidence of a malignancy was found. Treatment consisting of a low-calcium CalciLo diet (in place of breast milk) adequately controlled the patient’s hypercalcaemia. Hypercalcaemia associated with CAKUT in infancy is not all that uncommon and was reported in 15/99 infants in another study, most of whom had a suppressed PTH similar to that of our patient. PTHrP was not measured in these cases and may have also been elevated.LimitationsThe study is limited in that it is a description of a single patient case. Future measurement of PTHrP in similar patients is necessary to confirm our results.ConclusionsThe possibility of elevated PTHrP levels must be considered in patients with known renal dysplasia who are differentially diagnosed with hypercalcaemia.

Esophageal Cancer Initially Presenting as Severe Paraneoplastic Hypercalcemia Requiring Hemodialysis

Paraneoplastic hypercalcemia without bone metastasis occurs rarely in esophageal cancer. A 75-year-old man was admitted for general weakness and lethargy. Laboratory data showed high serum calcium level (corrected calcium 14.6 mg/dL), low parathyroid hormone level (3.3 pg/mL) and high parathyroid hormone-related peptide level (3.5 pmol/L). Esophagogastroscopy showed a malignant tumor in the esophagus. Histology showed moderately differentiated squamous cell carcinoma. Bone scan showed no evidence of bone metastasis. Since the patient's calcium levels remained high and mental state did not show improvement despite intravenous fluid therapy, diuretics and intravenous bisphosphonate, hemodialysis was started. After hemodialysis treatment, the serum calcium level subsequently normalized and his mental status improved. Herein, we report a rare case of paraneoplastic hypercalcemia in a patient with esophageal cancer.

Regulation of chondrocyte differentiation by IRE1α depends on its enzymatic activity

Bone morphogenetic protein 2(BMP2) is known to activate unfolded protein response (UPR) signal molecules in chondrogenesis. Inositol-requiring enzyme-1α (IRE1α),as one of three unfolded protein sensors in UPR signaling pathways, can be activated during ER stress. However, the influence on IRE1α in chondrocyte differentiation has not yet been elucidated. Here we present evidence demonstrating that overexpression of IRE1α inhibits chondrocyte differentiation, as revealed by reduced expression of collagen II (ColII), Sox9, collagen X (ColX), matrix metalloproteinase 13 (MMP-13), Indian hedgehog (IHH), Runx2 and enhanced expression of parathyroid hormone-related peptide (PTHrP). Furthermore, IRE1α-mediated inhibition of chondrogenesis depends on its enzymatic activity, since its point mutant lacking enzymatic activity completely loses this activity. The RNase and Kinase domains of IRE1α C-terminal are necessary for its full enzymatic activity and inhibition of chondrocyte differentiation. Mechanism studies demonstrate that granulin–epithelin precursor(GEP), a growth factor known to stimulate chondrogenesis, induced IRE1α expression in chondrogenesis. The expression of IRE1α is depended on GEP signaling, and IRE1α expression is hardly detectable in GEP−/− embryos. In addition, IRE1α inhibits GEP-mediated chondrocyte differentiation as a negative regulator. Altered expression of IRE1α in chondrocyte hypertrophy was accompanied by altered levels of IHH and PTHrP. Collectively, IRE1α may be a novel regulator of chondrocyte differentiation by 1) inhibition GEP-mediated chondrocyte differentiation as a negative regulator; 2) promoting IHH/PTHrP signaling.

Ovarian carcinoma producing parathyroid hormone-related protein causing hypercalcemia and metastatic calcification detected on 18 F-FDG PET-CT

Hypercalcemia is associated with gynecologic malignant diseases, and cases involving various organs such as the uterus, ovaries, vulva, and vagina. This may be due to elevated levels of parathyroid hormone-related peptide (PTHrP). We describe here two cases of ovarian carcinoma simultaneously producing PTHrP that caused hypercalcemia and metastatic calcification detected on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT).

XBP1S Associates with RUNX2 and Regulates Chondrocyte Hypertrophy

BMP2 (bone morphogenetic protein 2) is known to activate unfolded protein response signaling molecules, including XBP1S and ATF6. However, the influence on XBP1S and ATF6 in BMP2-induced chondrocyte differentiation has not yet been elucidated. In this study, we demonstrate that BMP2 mediates mild endoplasmic reticulum stress-activated ATF6 and directly regulates XBP1S splicing in the course of chondrogenesis. XBP1S is differentially expressed during BMP2-stimulated chondrocyte differentiation and exhibits prominent expression in growth plate chondrocytes. This expression is probably due to the activation of the XBP1 gene by ATF6 and splicing by IRE1a. ATF6 directly binds to the 5'-flanking regulatory region of the XBP1 gene at its consensus binding elements. Overexpression of XBP1S accelerates chondrocyte hypertrophy, as revealed by enhanced expression of type II collagen, type X collagen, and RUNX2; however, knockdown of XBP1S via the RNAi approach abolishes hypertrophic chondrocyte differentiation. In addition, XBP1S associates with RUNX2 and enhances RUNX2-induced chondrocyte hypertrophy. Altered expression of XBP1S in chondrocyte hypertrophy was accompanied by altered levels of IHH (Indian hedgehog) and PTHrP (parathyroid hormone-related peptide). Collectively, XBP1S may be a novel regulator of hypertrophic chondrocyte differentiation by 1) acting as a cofactor of RUNX2 and 2) affecting IHH/PTHrP signaling.

Hypercalcemia in Disseminated Coccidioidomycosis: Expression of Parathyroid Hormone-Related Peptide Is Characteristic of Granulomatous Inflammation

Hypercalcemia is an uncommon complication of disseminated granulomatous infections. The pathogenesis of hypercalcemia associated with infection is not clear. We investigated a case of disseminated coccidioidomycosis with hypercalcemia. We used a sensitive radioimmunoassay to measure serum parathyroid hormone-related peptide (PTHrP) and a mouse monoclonal antibody to PTHrP to immunostain biopsies. We found elevated serum levels of PTHrP while the patient was hypercalcemic that became undetectable when serum calcium normalized. We also found that the inflammatory cells and some surrounding tissues in skin biopsies expressed PTHrP. PTHrP was expressed by all biopsied lesions of patients with coccidioidomycosis that we examined, whether localized to the lung or disseminated, but no other cases were hypercalcemic. PTHrP was also expressed by the 3 mycobacterial granulomas we examined, and in a lymph node from a patient with sarcoidosis. The expression of PTHrP is a property of infectious granulomas regardless of etiology or the tissue involved, suggesting that PTHrP expression is part of the normal granulomatous immune response. Hypercalcemia may result if there is disseminated infection and multiple granulomas. We propose that excess production of PTHrP is the cause of hypercalcemia in granulomatous infections.

Gene and protein expression of cartilage canal and osteochondral junction chondrocytes and full-thickness cartilage in early equine osteochondrosis

The objective of this study was to investigate the expression of several regulatory factors associated with cartilage maturation in horses with early osteochondrosis (OC) compared to normal controls. The hypothesis was that expression levels of Indian hedgehog (Ihh), parathyroid hormone-related peptide (PTH-rP), vascular endothelial growth factor (VEGF), platelet-derived growth factor-A (PDGF-A), and matrix metalloproteinase-13 and -3 (MMP-13, -3) would be increased in OC. Articular cartilage and osteochondral samples were collected from the femoropatellar joints from seven OC and eight normal young (1-6 months) horses after euthanasia and snap frozen or suspended in 4% paraformaldehyde. Laser capture microdissection was used to capture cells surrounding cartilage canals and the osteochondral junction. Total RNA was isolated from whole cartilage and laser-captured cells. Equine-specific Ihh, PTH-rP, VEGF, PDGF-A, MMP-13, and MMP-3 mRNA expression levels were evaluated by real-time (RT)-PCR. Spatial tissue protein expression was determined by immunohistochemistry. In laser-captured samples, there was significantly increased MMP-13 and PDGF-A gene expression in chondrocytes adjacent to cartilage canals and increased PDGF-A gene expression in osteochondral junction chondrocytes of OC-affected foals. In full-thickness cartilage samples, there was significantly increased Ihh, MMP-3, and MMP-13 gene expression in OC samples, while PTH-rP protein expression was significantly higher along the osteochondral junction. The results suggest that pathways involving cartilage maturation and ossification are altered in early OC and may be associated with disease pathogenesis.

Parathyroid hormone‐related peptide‐producing non‐familial pheochromocytoma in a child

We experienced a case of parathyroid hormone-related peptide (PTHrP)-producing pheochromocytoma, which was found in a 12-year-old boy with hypercalcemia. The leading symptom was abdominal pain, and severe hypertension and tachycardia were noticed at the initial visit. His medical and familial histories were unremarkable. Laboratory examinations showed hypercalcemia (3.3 mmol/L of serum-calcium). Computed tomography showed a heterogeneous mass measuring 5.0 cm in the right adrenal gland, which had abnormal uptake with 123-I metaiodobenzylguanidine scintigraphy. Serum/urine catecholamines were highly elevated, and serum PTHrP also increased (1.4 pmol/L). The patient underwent laparoscopic right adrenalectomy. The tumor was histologically diagnosed as typical pheochromocytoma and the expression of PTHrP was confirmed with immunohistochemistry. The serum PTHrP level was normalized after surgery. He was free of disease postoperatively for 12 months. There has been no described pediatric patient with PTHrP-producing pheochromocytoma. We showed evidence that the present tumor is a complex neoplasm involving various neuroendocrine activities with the dual-lineage differentiation.

Parathyroid Hormone-Related Peptide and Parathyroid Hormone-Related Peptide Receptor Type 1 Expression in Human Lung Adenocarcinoma

In many primary tumors, parathyroid hormone-related peptide (PTHrP) and PTHrP type 1 receptor (PTH1R) are coexpressed, supporting the possibility that PTHrP/PTH1R system can mediate important signals for tumor progression through paracrine/autocrine mechanisms. In non-small cell lung carcinoma the clinical relevance of the expression of PTH1R remains to be investigated. Fifty-four lung adenocarcinomas of mixed histologic type from patients with stage I and II cancer were assayed by quantitative immunohistochemistry for the expression of PTHrP and PTH1R. PTHrP and PTH1R were expressed in a wide range of intensity in the cytoplasm of tumor cells, and their values showed a positive correlation. PTH1R, but not PTHrP, was expressed by plasma cells infiltrating the tumor stroma. PTHrP and PTH1R were not associated with age, tumor diameter, or histopathologic grading, whereas they were directly associated with lymph node involvement at presentation. Cox regression analysis, using PTHrP and PTH1R as continuous covariates, showed that the covariate levels were directly associated with the risk of death and metastasis. Patients whose tumors coexpressed high levels of PTHrP and PTH1R showed the highest risk of metastasis (relative risk, 5.89; 95% CI, 2.1-16.6; P = .0003) and death (relative risk, 6.24; 95% CI, 1.6-23.9; P = .0033). The presence of PTH1R-positive plasma cells in the tumor stroma was associated with a more favorable survival rate independently from the PTHrP status of the tumor. The paracrine/autocrine signaling through PTHrP/PTH1R could be important in early-stage lung adenocarcinoma progression.

Multiple osteolytic bone lesions with high serum levels of interleukin‐6 and CCL chemokines in a patient with adult T cell leukemia

A 37-year-old woman was diagnosed as having chronic adult T-cell leukemia (ATL) of the skin by a skin biopsy and human T-cell leukemia virus type-1 serology at our hospital in August 1992. The skin lesions of ATL were improved by treatment with psoralen ultraviolet ray A. She complained of severe pain in her bilateral forearms, hands and ankles, and X-ray examination in July 1999 revealed multiple punched-out lesions of the extremities. Serum levels of parathyroid hormone-related peptide, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha and total serum receptor activator of nuclear factor kappaB ligand were not elevated. However, serum levels of IL-6, CCL2 monocyte chemoattractant protein-1 (MCP-1), CCL3 [macrophage inflammatory protein-1alpha (MIP-1alpha)] and CCL4 (MIP-1beta) were markedly elevated. Here, we have discussed the possible mechanism underlying the onset of the osteolytic lesions.

Blocking Ihh signaling pathway inhibits the proliferation and promotes the apoptosis of PSCs

The roles of Indian hedgehog (Ihh) signaling pathway in the proliferation and apoptosis of precartilaginous stem cells (PSCs) were investigated. PSCs, labeled with fibroblast growth factor receptor 3 (FGFR-3), were isolated from neonatal rats by immunomagnetic separation. After identification with FGFR-3 and Col II, the cells were incubated with different concentrations of cyclopamine (cyclo), the specific inhibitor of Ihh signaling pathway. The morphologic changes of the cells were observed under the inverted phase contrast microscope. The mRNA expression levels of Ihh, parathyroid hormonerelated peptide (PTHrP), protein Patched (Ptch), Bcl-2 and p21 were detected by RT-PCR. The protein expression levels of Ihh and Ptch were measured by Western blot. MTT assay was used to examine the effects of cyclo on proliferation of PSCs. Apoptosis rate of PSCs was examined by Annexin V/PI assay of flow cytometric analyses. After PSCs were incubated with cyclo, obvious morphologic changes were observed as compared with the control group. The mRNA expression levels of PTHrP, Ptch and Bcl-2 were decreased to varying degrees in a cyclo dose-dependent manner. However, the expression levels of Ihh and p21 mRNA were increased. The protein expression of Ptch and Ihh had the same change as the mRNA expression. Meanwhile, cyclo could obviously inhibit the proliferation and promote the apoptosis of PSCs. The results indicated that Ihh signaling pathway plays an important role in regulating the proliferation and apoptosis of PSCs, which is probably mediated by Bcl-2 and p21.

CFTR and Wnt/beta-catenin signaling in lung development

BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) was shown previously to modify stretch induced differentiation in the lung. The mechanism for CFTR modulation of lung development was examined by in utero gene transfer of either a sense or antisense construct to alter CFTR expression levels.The BAT-gal transgenic reporter mouse line, expressing β-galactosidase under a canonical Wnt/β-catenin-responsive promoter, was used to assess the relative roles of CFTR, Wnt, and parathyroid hormone-related peptide (PTHrP) in lung organogenesis. Adenoviruses containing full-length CFTR, a short anti-sense CFTR gene fragment, or a reporter gene as control were used in an intra-amniotic gene therapy procedure to transiently modify CFTR expression in the fetal lung.ResultsA direct correlation between CFTR expression levels and PTHrP levels was found. An inverse correlation between CFTR and Wnt signaling activities was demonstrated.ConclusionThese data are consistent with CFTR participating in the mechanicosensory process essential to regulate Wnt/β-Catenin signaling required for lung organogenesis.