对有效的抗肿瘤单抗药物的探索

文章综述了单抗药物用于临床肿瘤治疗的研究进展。开发一个成功的抗肿瘤单抗药物应从以下几方面考虑 :(1)选择特异的肿瘤抗原 ;(2 )制备人源化单抗以降低单抗药物的免疫原性 ;(3)利用抗体工程改造抗体结构以延长半衰期 ;(4)改进给药方式以提高抗体药物在肿瘤组织的局部浓度 ;(5 )提高单抗药物的抗肿瘤活性 ;(6 )进一步提高单抗药物的选择性。还简述了单抗药物抗肿瘤的可能机制及单抗药物的前景展望。

Surgical solutions to the problem of massive weight loss

In response to the global rise in obesity, bariatric surgery has become increasingly more popular and successful As a result, the demand for body contouring following massive weight loss is rapidly growing. Although bariatric procedures may produce impressive weight loss, people who achieve massive weight loss are often unhappy with the hanging folds of skin and subcutaneous tissue that remain. This review examines the nature of the post-bariatric deformity in each body region and briefly reviews common approaches to their treatment.

Peroxisome proliferator-activated receptor γ agonist reduces the severity of post-ERCP pancreatitis in rats

AIM： To determine the effects of prophylactic peroxisome proliferator-activated receptor （PPARy） agonist administration in an experimental model of post-endoscopic retrograde cholangiopancreatography （post-ERCP） acute pancreatitis. METHODS： Post-ERCP pancreatitis was induced in male Wistar rats by infusion of contrast medium into the pancreatic duct. In additional group, rosiglitazone, a PPARγ agonist, was administered 1 h before infusion of contrast medium. Plasma and pancreas samples were obtained 6 h after the infusion. RESULTS： Infusion of contrast medium into the pancreatic duct resulted in an inflammatory process characterized by increased lipase levels in plasma, and edema and myeloperoxidase activity （MPO） in pancreas. This result correlated with the activation of nuclear factor κB （NFκB） and the inducible NO synthase （iNOS） expression in pancreatic cells. Rosiglitazone reduced the increase in lipase and the level of edema and the increase in myeloperoxidase as well as the activation of NFκB and iNOS expression. CONCLUSION： A single oral dose of rosiglitazone, given 1 h before post-ERCP pancreatitis induction is effective in reducing the severity of the subsequent inflammatory process. The protective effect of rosiglitazone was associated with NFκB inhibition and the blockage of leukocyte infiltration in pancreas.

A clinical trial of combined use of rosiglitazone and 5-aminosalicylate for ulcerative colitis

AIM: To investigate the therapeutic effects of the combined use of rosiglitazone and aminosalicylate on mild or moderately active ulcerative colitis (UC).METHODS: According to the national guideline for diagnosis and treatment of inflammatory bowel disease (IBD) in China, patients with mild or moderately active UC in our hospital were selected from July to November, 2004. Patients with infectious colitis, amoebiasis, or cardiac, renal or hepatic failure and those who had received corticosteroid or immunosuppressant treatment within the last month were excluded. Following a quasi-randomization principle, patients were allocated alternatively into the treatment group (TG) with rosiglitazone 4 mg/d plus 5-ASA 2 g/d daily or the control group (CG) with 5-ASA 2 g/d alone, respectively, for 4 wk. Clinical changes were evaluated by Mayo scoring system and histological changes by Truelove-Richards' grading system at initial and final point of treatment.RESULTS: Forty-two patients completed the trial, 21 each in TG and CG. The Mayo scores in TG at initial and final points were 5.87 (range: 4.29-7.43) and 1.86 (range: 1.03-2.69) and those in CG were 6.05 (range: 4.97-7.13) and 2.57 (range: 1.92-3.22) respectively. The decrements of Mayo scores were 4.01 in TG and 3.48 in CG, with a remission rate of 71.4% in TG and 57.1% in CG, respectively. Along with the improvement of disease activity index (DAI), the histological grade improvement was more significant in TG than in CG (P < 0.05).CONCLUSION: Combined treatment with rosiglitazone and 5-ASA achieved better therapeutic effect than 5-ASA alone without any side effects. Rosiglitazone can alleviate colonic inflammation which hopefully becomes a novel agent for UC treatment.

Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage

The release of proinfammatory cytokines during infam-mation represents an attempt to respond to injury, but it may produce detrimental effects. The infammasome is a large, multiprotein complex that drives proinfammatory cytokine production in response to infection and tissue injury; the best-characterized inflammasome is the nod-like receptor protein-3 （NLRP3）. Once activated, infammasome leads to the active form of caspase-1, the enzyme required for the maturation of interleukin-1beta. Additional mechanisms bringing to renal inflammatory, systemic diseases and fibrotic processes were recently reported, via the activation of the inflammasome that consists of NLRP3, apoptosis associated speck-like protein and caspase-1. Several manuscripts seem to identify NLRP3 infammasome as a possible therapeutic target in the treatment of progressive chronic kidney disease. Serum amyloid A （SAA）, as acute-phase protein with also proinfammatory properties, has been shown to induce the secretion of cathepsin B and infammasome components from human macrophages. SAA is a well recognised potent activator of the NLRP3. Here we will address our description on the involvement of the kidney in autoinflammatory diseases driven mainly by secondary, or reactive, AA amyloidosis with a particular attention on novel therapeutic approach which has to be addressed in suppressing underlying inflammatory disease and reducing the SAA concentration.

Plasma leptin and ghrelin concentrations in patients with Crohn's disease

AIM: To determine the concentrations of leptin and ghrelin, which have opposite effects on appetite,energy expenditure, and weight control, in the plasma of patients with Crohn's disease (CD), which is often associated with weight loss and malnutrition.METHODS: Plasma leptin and ghrelin concentrations were determined in 28 outpatients with CD by radioimmunoassay. Age- and sex-matched controls with and without Helicobacter pylori(H pylori) infection (28for each) were enrolled in the study. Circulating levels of these hormones were assessed with respect to CD activity, disease localization and medical treatment.RESULTS: There were no significant differences in ghrelin levels between CD patients and H pylorinegative controls. However, circulating ghrelin levels were significantly lower in H pylori-infected subjects than in CD patients and uninfected controls. Plasma leptin levels were comparable among the groups. Localization and medication profile had no significant impact on circulating ghrelin and leptin levels.CONCLUSION: Apart from H pyloriinfection, CD itself has no significant influence on circulating ghrelin and leptin levels in the outpatients who were mostly in inactive state.

Roles of the (pro) renin receptor in the kidney

Prorenin receptor （PRR） is a multi-functioning protein possessing at least four different roles： （1） working as a receptor for renin and prorenin producing angiotensin I from angiotensinogen thus enhancing the tissue renin-angiotensin system; （2） inducing intracellular signals when a ligand binds to PRR; （3） participating in the functions of vacuolar proton ATPase; and （4） constitut-ing the Wnt signaling receptor complex. Here, the roles of PRR in kidney physiology and diabetic conditions as well as recent fndings regarding a soluble form of PRR are discussed. We also propose the possible mechanism concerning diabetic nephropathy as “trade-off hypothe-sis” from a PRR point of view. In brief, under hypergly-cemic conditions, injured podocytes degrade degener-ated proteins and intracellular organelles which require V-ATPase and PRR for vesicle internal acidification. Sustained hyperglycemia overproduces PRR molecules, which are transported to the transmembrane and bind to increased serum prorenin in the diabetic condition. This enhances tissue renin-angiotensin system and PRR-mediated mitogen-activated protein kinase signals, resulting in increased injurious molecules such as transforming growth factor-β, cyclooxygenase2, interleukin1β, and tumor necrosis factor-α ending in diabetic ne-phropathy progression. Although many fndings led us to better PRR understanding, future works should elu-cidate which PRR functions, of the four discussed here, are dominant in each cell and kidney disease context.

DIAGNOSIS AND TREATMENT OF PULMONARY HAMARTOMA

From 1970 to 1997, 67 patients with pulmonary hamartoma were operated on in our hospital. There were 38 men and 29 women with a M/F ratio of 1. 3: 1. The mean age was 47 years (range 21 to 82 years). The peak incidence was 40 to 60 years. 39% Patients had pulmonary symptoms: hemoptysis, cough, phlegm and chest pain. All were solitary. 68. 7% tumors were located in right lung and 64. 2% in upper or middle lobe. 80. 6% hamartomas were less than 3 cm in transverse diameter. On chest films, the opacity was homogeneous in 79.1% cases, heterogeneous in 20.9% and calcifications in 9.0%. The vast majority of shadows were heterogeneous on CT films. Operation is the best treatment for hamartomas. Postoperative mortality was 1. 5%. There was none recurrences and canceration during the follow-up (mean 14 years).

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rodent models of autosomal recessive polycystic kidney disease （ARPKD）. METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day（PN） 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model （from PN30 to PN90） to assess effcacy and toxicity in animals where developmental processes are complete. The following parameters were assessed： Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by： Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis （active VEGFR2/KDR） was assessed by Western analysis.RESULTSThis study demonstrates that： （1） in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis： EGFR, ErbB2, c-Src and KDR; and （2） this reduction of kinase activity resulted in signifcant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.

Advanced wasting in peritoneal dialysis patients

AIM To identify patients with end-stage renal disease treated by peritoneal dialysis(PD) who had zero body fat(BF) as determined by analysis of body composition using anthropometric formulas estimating body water(V) and to compare nutritional parameters between these patients and PD patients whose BF was above zero.METHODS Body weight(W) consists of fat-free mass(FFM) andBF.Anthropometric formulas for calculating V allow the calculation of FFM as V/0.73,where 0.73 is the water fraction of FFM at normal hydration.Wasting from loss of BF has adverse survival outcomes in PD.Advanced wasting was defined as zero BF when V/0.73 is equal to or exceeds W.This study,which analyzed 439 PD patients at their first clearance study,used the Watson formulas estimating V to identify patients with V_(Watson)/0.73 ≥ W and compared their nutritional indices with those of PD patients with V_(Watson)/0.73 < W.RESULTS The study identified at the first clearance study two male patients with V_(Watson)/0.73 ≥ W among 439 patients on PD.Compared to 260 other male patients on PD,the two subjects with advanced wasting had exceptionally low body mass index and serum albumin concentration.The first of the two subjects also had very low values for serum creatinine concentration and total(in urine and spent peritoneal dialysate) creatinine excretion rate while the second subject had an elevated serum creatinine concentration and high creatinine excretion rate due,most probably,to non-compliance with the PD prescription.CONCLUSION Advanced wasting(zero BF) in PD patients,identified by the anthropometric formulas that estimate V,while rare,is associated with indices of poor somatic and visceral nutrition.

Telomerase activity: An attractive target for cancer therapeutics

Telomeres are non-coding tandem repeats of 1000-2000 TTAGGG nucleotide DNA sequences on the 3’ termini of human chromosomes where they serve as protective “caps” from degradation and loss of genes. The “cap” at the end of chromosome required to protect its integ-rity is a 150-200 nucleotide-long single stranded G-rich 3’ overhang that forms two higher order structures, a T-loop with Sheltering complex, or a G-quadruplex com-plex. Telomerase is a human ribonucleoprotein reverse transcriptase that continually added single stranded TTAGGG DNA sequences onto the single strand 3’ of telomere in the 5’ to 3’ direction. Telomerase activity is detected in male germ line cells, proliferative cells of renewal tissues, some adult pluripotent stem cells, embryonic cells, but in most somatic cells is not de-tected. Re-expression or up-regulation of telomerase in tumours cells is considered as a critical step in cell tumorigenesis and telomerase is widely considered as a tumour marker and a target for anticancer drugs. Dif-ferent approaches have been used in anticancer thera-peutics targeting telomerase. Telomerase inhibitors can block directly Human TElomerase Reverse Transcrip-tase （hTERT） or Human TElomerase RNA telomerase subunits activity, or G-quadruplex and Sheltering complex components, shortening telomeres and inhibiting cell proliferation. Telomerase can become an immune target and GV1001, Vx-001, I540 are the most wide-spread vaccines used with encouraging results. Another method is to use hTERT promoter to drive suicide gene expression or to control a lytic virus replication. Recently telomerase activity was used to activate pro-drugs such as Acycloguanosyl 5’-thymidyltriphosphate, a synthetic ACV-derived molecule when it is activated by telomer-ase it does not require any virus or host active immune response to induce suicide gene therapy. Advantage of all these therapies is that target only neoplastic cells without any effects in normal cells, avoiding toxicity and adverse effects of the current chemotherapy. However, as not all the approaches are equally effcient, further studies will be necessary.

Adult stem cells as a tool for kidney regeneration

Kidney regeneration is a challenging but promisingstrategy aimed at reducing the progression to end-stagerenal disease （ESRD） and improving the quality of life of patients with ESRD. Adult stem cells are multipotent stem cells that reside in various tissues, such as bone marrow and adipose tissue. Although intensive studies to isolate kidney stem/progenitor cells from the adult kidney have been performed, it remains controversial whether stem/progenitor cells actually exist in the mammalian adult kidney. The effcacy of mesenchymal stem cells （MSCs） in the recovery of kidney function has been demonstrated in animal nephropathy models, such as acute tubular injury, glomerulonephritis, renal artery stenosis, and remnant kidney. However, their benefcial effects seem to be mediated largely via their paracrine effects rather than their direct differentiation into renal parenchymal cells. MSCs not only secrete bioactive molecules directly into the circulation, but they also release various molecules, such as proteins, mRNA, and microRNA, in membrane-covered vesicles. A detailed analysis of these molecules and an exploration of the optimal combination of these molecules will enable the treatment of patients with kidney disease without using stem cells. Another option for the treatment of patients with kidney disease using adult somatic cells is a direct/indirect reprogramming of adult somatic cells into kidney stem/progenitor cells. Although many hurdles still need to be overcome, this strategy will enable bona fde kidney regeneration rather than kidney repair using remnant renal parenchymal cells.

Antineutrophil cytoplasmic antibodies crescentic allograft glomerulonephritis after sofosbuvir therapy

Antineutrophil cytoplasmic antibodies(ANCA) are well known to be associated with several types of vasculitis, including pauci-immune crescentic glomerulonephritis, a form of rapid progressive glomerular nephritis(RPGN). ANCA vasculitis has also been reported after administration of propylthiouracil, hydralazine, cocaine(adulterated with levimasole), allopurinol, penicillamine and few other drugs. All previously reported cases of drug-associated ANCA glomerulonephritis were in native kidneys. Sofosbuvir is a new and effective drug for hepatitis C virus infection. Here, we report a case of ANCA vasculitis and RPGN following sofosbuvir administration in a kidney transplant recipient. It also represents the first case of drug-associated ANCA vasculitis in a transplanted kidney. Further drug monitoring is necessary to elucidate the degree of association and possible causal effect of sofosbuvir and perinuclear ANCA vasculitis.

Anti-Hepatitis B Virus Drugs in Clinical and Preclinical Development

Up to date, there are two types of drugs approved to treat hepatitis B： interferons and nucleos （t） ide analogues. However, the therapies are limited in the clinical context because of the negative side effects of interferon-or and the development of substantial viral resistance to nucleos （t） idic inhibitors. Therefore, new drugs with novel structures and mechanisms are needed. In this article, the drugs approved by FDA or the European Commission for treating chronic hepatitis B virus infection, as well as those under clinical trials, and several compounds in preclinical studies are reviewed. Additionally, some potential targets and strategies to combat chronic hepatitis B virus infection are discussed.

Chlamydia pneumoniae replicates in Kupffer cells in mouse model of liver infection

AIM: To develop an animal model of liver infection with Chlamydia pneumoniae (C. pneumoniae) in intraperito-neally infected mice for studying the presence of chlamy-diae in Kupffer cells and hepatocytes.METHODS: A total of 80 BALB/c mice were inoculated intraperitoneally with C. pneumoniae and sacrificed at various time points after infection. Chlamydiae were looked for in liver homogenates as well as in Kupffer cells and hepatocytes separated by liver perfusion with collagenase. C. pneumoniae was detected by both isola-tion in LLC-MK2 cells and fluorescence in situ hybridiza-tion (FISH). The releasing of TNFA-α by C. pneumoniae in vitro stimulated Kupffer cells was studied by enzyme-linked immunosorbent assay.RESULTS: C. pneumoniae isolation from liver homoge-nates reached a plateau on d 7 after infection when 6 of 10 animals were positive, then decreased, and became negative by d 20. C. pneumoniae isolation from sepa-rated Kupffer cells reached a plateau on d 7 when 5 of 10 animals were positive, and became negative by d 20. The detection of C. pneumoniae in separated Kupffer cells by FISH, confirmed the results obtained by culture. Isolated hepatocytes were always negative. Stimula-tion of Kupffer cells by alive C. pneumoniae elicited high TNF-α levels. CONCLUSION: A productive infection by C. pneumo-niae may take place in Kupffer cells and C. pneumoniae induces a local pro-inflammatory activity. C. pneumoniae is therefore, able to act as antigenic stimulus when local-ized in the liver. One could speculate that C. pneumoniaeinfection, involving cells of the innate immunity such as Kupffer cells, could also trigger pathological immune re-actions involving the liver, as observed in human patients with primary biliary cirrhosis.

Late course three-dimensional conformal radiotherapy for esophageal carcinoma

Objective： The aim of our study was to evaluate the clinical results and acute side effects of late course three-dimensional conformal radiotherapy （3DCRT） for esophageal carcinoma. Methods： From January 2004 to October 2006, 70 patients with esophageal carcinoma received late course 3DCRT. Their clinical data were analyzed retrospectively. The short-term clinical results, acute side effects, local control rates and survival rates were evaluated. Results： The complete response rate was 62.9%, partial response rate was 35.7%, and the overall response rate was 98.6%. The 1-, 2-and 3-year local control rates were 77.1%, 51.4% and 45.7%, respectively. The 1-, 2-and 3-year overall survival rates were 75.7%, 54.3% and 38.6%, respectively. The median survival time was 26 months. Conclusion： The technique of late course 3DCRT is an effective treatment for esophageal carcinoma and tend to improve the overall survival rate.

Screening and diagnosis of endometrial cancer in Lynch syndrome

Lynch syndrome （LS） is an autosomal dominant inherited cancer predisposition syndrome caused by a mismatch of DNA repair （MMR system）. Lifetime risk of developing endometrial and ovarian cancer in LS is higher than in the general population and gynecologic screening appears interesting. Screening is based on several tests： pelvic ultrasound, endometrial biopsy and hysteroscopy for endometrial cancer, pelvic ultrasound and CA125 for ovarian cancer. Those tests appear efficient for the diagnosis of gynecologic cancers in LS. Nevertheless, screening tests have not proved clinical benefit until now, and potential problems of compliance, risk of false negative cases, and interval cancer associated with screening do justify offering prophylactic surgery to patients. Women with LS should be informed of the potential benefits and risks of screening and the importance of evaluation in case of gynecologic symptoms or abnormal bleeding. Chemoprevention by progestin-containing oral contraceptives and the treatment ofthe potential benefits and risks of screening and the importance of evaluation in case of gynecologic symptoms or abnormal bleeding. Chemoprevention by progestin-containing oral contraceptives and the treatment of premalignant lesion are available options for reducing the risk of endometrial cancer in LS population.

A Case Report on Pulmonary Chemodectoma

A 36-year old female patient was admitted to our hospital in October 2005, with symptoms of cough and phlegmatic stagnation plus chest distress for over 5 months. She had received an X-ray examination at a local hospital before her hospitalization, and it was Shown that there was a small round-like pulmonary focus. No improvement was found after a pre-antiinflammatory treatment for the cough.

Neoadjuvant chemotherapy for osteosarcoma of the extremity: Outcome of the Chinese 1st protocol in a single institute

Objective： The aim of this study was to determine stand protocol for patients with extremity osteosarcoma by case following up after neoadjuvant chemotherapy and limb salvage operation. Methods： Between January 2000 and January 2007, 121 patients with extremity osteosarcoma were eligible for this analysis. After being graded according to Enneking classification, all patients were preoperative chemotherapy （methotrexate, cisplatin, doxorubicin, and ifosfamide. Some patients with liB tumors received extra interventional embolism）. And postoperatively, the same protocols were employed, but poor responders （tumor necrosis 〈 95%） received more treatment cycles than good responders and took some new medicine in place of the former one. Most of patients underwent limb salvage operation （99/121）, and the Musculoskeletal Tumor Society Score （MSTS） was used to evaluate the recovery of their limb functions. Results： The followed up last for average 37.3 months （range： 16-101 months）. Most patients （76/121） survived, and the overall survival （OS） was 62.8%. Forty-seven of the 121 patients underwent osteoarticular allografts, among which 12 cases of disunion between the host bone and graft bone, 4 cases of allograft absorption and 3 local recurrences appeared. The mean MSTS score was 22.6 ± 4.13, with an excellent limb function in 17 patients, good in 19 patients, fair in 6 patients and poor in 7 patients. The overall excellent and good function outcome was obtained in 76.6% of the patients. Fifty-two of 121 patients underwent custom-made or modular tumor endoprosthesis replacememt, among which 1 case of aseptic loosening, 1 case of peri-prosthesis infection and 4 local recurrences appeared. The mean MSTS was 24.32 ＋ 3.85, with an excellent limb function in 28 patients, good in 16 patients, fair in 5 patients and poor in 3 patients. The overall excellent and good function outcome was obtained in 84.6% of the patients. Conclusion： Neoadjuvant chemotherapy and limb salvage surgery are effective methods to treat osteosarcoma at present, although some patients still dying from postoperative metastases. Therefore, early diagnosis individualized treatment and exploring for new and effective therapeutic strategy should be the key to an ideal treatment for osteosarcoma.

New SLC12A3 disease causative mutation of Gitelman's syndrome

Gitelman's syndrome(GS) is a salt-losing tubulopathy with an autosomal recessive inheritance caused by mutations of SLC12A3, which encodes for the thiazidesensitive Na Cl cotransporter. In this study we report a new mutation of SLC12A3 found in two brothers affected by GS. Hypokalemia, hypocalciuria and hyperreninemia were present in both patients while hypomagnesemia was detected only in one. Both patients are compound heterozygotes carrying one well known GS associated mutation(c.2581 C > T) and a new one(c.283 del C) in SLC12A3 gene. The new mutation results in a possible frame-shift with a premature stopcodon(pG ln95 Argfs X19). The parents of the patients, heterozygous carriers of the mutations found in SLC12A3, have no disease associated phenotype. Therefore, the new mutation is causative of GS.