2015年 · 第95卷第02期

Cancer is a major disease that endangers human health. In 2010, the incidence rate of cancer in China was 235.23/100,000, and the mortality rate was 148.81/100,000, ranking first as the cause of death^[1]。 Drug therapy is an important means of tumor treatment, and the development of new anti-tumor drugs is an urgent clinical need. Clinical trials are the fastest, safest and most effective way to find new anti-tumor drugs, and at the same time, they provide the best treatment for cancer patients. Because new drugs do not have any data and experience on the human body before entering clinical trials, clinical evaluation is full of unknowns, and the risks and challenges are extremely high. Due to the lack of unified scientific standards in ethical review, efficacy and safety evaluation, painful lessons have taken place in the history of drug research and development in the world.

World Health Organization (WHO) Global Cancer Annual Report 2014^[1]: The total incidence, total death and incidence growth rate of malignant tumors in China ranked first in three items, but the 5-year survival rate is far lower than that of developed countries in Europe and America (30% and 60%). Compared with other malignant tumors, the incidence and mortality of pancreatic cancer are increasing faster, and it has ranked 7th and 6th among malignant tumors in China respectively^[2]； By 2030, the mortality rate of pancreatic cancer patients is expected to reach the second place among malignant tumors^[3]。 Extremely poor treatment effect and 5-year survival rate for pancreatic cancer<5%, one of the reasons is the irregularity of treatment. The problems related to the diagnosis and treatment of pancreatic cancer are described below.

A 51-year-old male patient. In February 2012, he went to the Institute of Hematology of Peking University due to low back pain for 2 months and right lower limb pain for 1 month. Blood routine: white blood cells 7.79×10⁹/L, absolute eosinophils (AEC) 1.96×10⁹/L, hemoglobin 122 g/L, platelets 132×10⁹/L. Biochemistry: serum calcium 1.47 mmol/L decreased (↓), creatinine 75 μ mol/L, albumin 33.5 g/L↓. Blood β 2 microglobulin 3.31 mg/L increased (↑), IgG 25.00 g/L↑, κ light chain 4.61 g/L↓, λ light chain 14.30 g/L↑, IgA 0.50 g/L↓, IgM 0.27 g/L↓. Blood M protein identification: IgG lambda type, M protein quantification was 14.69 g/L. No abnormalities were observed by urinary immunofixation electrophoresis. Anterior and lateral X-ray films of the skull showed diffuse perforated bone destruction of different sizes in the skull, which was consistent with multiple myeloma (MM). Pelvic CT: Multiple round low-density foci were seen in lumbar vertebra, sacral vertebra, ilium, pubic bone, ischium and bilateral femur. Morphology of bone marrow cells: hyperplasia grade V, granulocyte 78%, eosinophilic proportion increased, accounting for 18%; Plasma cells accounted for 3%. Immunotyping of bone marrow cells: Abnormal clonal plasma cells expressed CD45dim, CD38, CD138, C λ, CD200, CD56, some cells expressed CD117, CD9, and eosinophils accounted for 22.43%. Bone marrow biopsy: Fibroblasts proliferate extensively, and lymphocyte-like plasma cells are diffused or distributed in patches, with different cell sizes, widened perinuclear bands in some cells, with foamy feeling, and occasionally binuclear. Karyotype analysis G banding: 46, XY [4]. Fluorescence in situ hybridization (FISH): No 1q21 amplification, 13q14.3 deletion, RB1 deletion, IgH rearrangement, P53 deletion were observed. The diagnosis was MM IgG type λ, Durie/Salmon (DS) stage IIIA/International Staging System (ISS) stage II. After that, TAD regimen (thalidomide + epirubicin + dexamethasone) was given to induction chemotherapy for a total of 4 courses. After the end of the first course of treatment, the AEC decreased to normal (AEC<0.50×10⁹/L). The AEC fluctuated slightly in the subsequent 3 courses, and the AEC could rise to 0.96×10 before chemotherapy⁹/L, AEC could be reduced to 0 after chemotherapy, and AEC continued to be at a normal level after the fourth course of treatment. The blood M protein quantification was 4.48 g/L after re-examination, and the efficacy evaluation reached partial remission (PR). Two more courses of TAD regimen were given for consolidation therapy, and then serum β 2 microglobulin 2.39 mg/L, IgG 8.91 g/L, and λ light chain 5.22 g/L were reexamined, all of which decreased significantly. M protein was not observed by serum protein electrophoresis, and monoclonal IgG λ was still observed by immunofixation electrophoresis. No abnormalities were observed in urine immunofixation electrophoresis. Efficacy was assessed as a very good partial response (VGPR).

Atherosclerosis is the most common cause of renal artery stenosis. Atherosclerotic renal artery stenosis (ARAS) accounts for 60% ~70% of all the causes of renal artery stenosis in China^[1]Whereas about 90% in European and American countries^[2]。 ARAS often occurs in older adults with a history of hypertension. In the hypertensive population, the literature reports that approximately 1% to 6% of patients have ARAS at the same time^[3]； The prevalence of ARAS in older adults over 65 years can be as high as 7%^[4]； Among patients undergoing cardiac catheterization, the prevalence of ARAS exceeds 30%; Among patients who already have atherosclerosis, the prevalence of ARAS exceeds 50%^[5]。 Recently Cooper et al.^[6]The results of a published large-scale prospective randomized controlled trial suggest that no significant benefit was observed in renal artery stenting on top of drug therapy compared with drug therapy alone. This new evidence raises serious questions about the place of renal artery stents in the treatment of ARAS. Are renal artery stents effective for ARAS? How should we decide whether to perform renal artery stenting in clinical treatment of ARAS patients? Or which subgroups of ARAS patients may benefit from renal artery stents? This paper summarizes this hot issue as follows.

The initiation of youth is influenced by the interaction of genetic, nutritional, environmental, social and psychological factors, etc. The biological manifestation is that the secretion frequency and amplitude of hypothalamic gonadotropin-releasing hormone (GnRH) increases, which stimulates the pituitary gland to synthesize and secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thus activating gonadal function. The development of secondary sexual characteristics before the age of 8 in girls and before the age of 9 in boys is called precocious puberty (PP). Precocious puberty induced by premature initiation of the hypothalamic-pituitary-gonadal axis is called GnRH-dependent precocious puberty (GDPP), also known as central precocious puberty (CPP). Central nervous system diseases, trauma, etc. can lead to CPP, but most patients can't find organic lesions, which are called idiopathic CPP (ICPP), of which the proportion of ICPP in girls can account for 90%. The consistency of adolescent developmental age in the same race or family indicates that genetic factors play an important role in the initiation of adolescence, and many scholars have been devoting themselves to the genetic basic research of ICPP. In this paper, the research progress of ICPP gene in recent years will be reviewed.

Long-chain non-coding RNAs (lncRNAs) are a class of RNAs with transcripts ranging from 200 nt to 100 kb in length, lacking a reading frame of significant length (less than 100 amino acids), regulating gene expression levels at various levels but not encoding proteins in the form of RNAs^[1,2]。 According to the relationship with the nearest encoding protein gene, lncRNA are divided into: (1) sense lncRNA, located in the same strand as the encoding protein gene; (2) an antisense lncRNA located in a strand distinct from that gene encoding the protein; (3) bidirectional lncRNA, which is dispersed or aggregated in the direction closest to the lncRNA of the encoding protein gene during transcription; (4) an intron lncRNA located within an intron of a gene encoding a protein; (5) Intergenic lncRNA, located in the intergenic region of the two encoded proteins^[3]。 Initially, lncRNAs were considered to be the "noise" of genome transcription, a by-product of RNA polymerase II transcription, and did not have any biological function. However, later studies have found that the expression of some lncRNAs is tissue-specific and spatiotemporal specific, and many lncRNAs have conserved secondary structures, suggesting that lncRNAs have important biological functions^[2,3]。 Current studies have shown that lncRNA is involved in the pathophysiological processes of many diseases, especially in many kinds of tumors^[4,5,6]。 In this paper, the research progress of the relationship between lncRNA and the occurrence, development, diagnosis, treatment and prognosis of gastric cancer in recent years is summarized as follows.

The endoplasmic reticulum, as a major site for secreted protein folding modification and calcium storage, plays a key role in maintaining cellular homeostasis. Endoplasmic reticulum homeostasis is disrupted such as misfolded protein aggregation, Ca^2＋Depletion and lipid synthesis disorders will trigger a series of intracellular responses, called endoplasmic reticulum stress (ERS), through corresponding signaling pathways. Among them, the research on unfolded protein response (UPR) is the most in-depth. In the respiratory system, ERS can play an antioxidant protective effect, and can also affect the expression of some important proteins in the lung, induce inflammation and apoptosis. These effects play an important role in the occurrence and development of various respiratory diseases, including chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, asthma and lung cancer. The biological effects of ERS in respiratory diseases are reviewed below.

A 58-year-old male, farmer, was admitted to the hospital on 28 November 2013 due to "blood in sputum for 1 week and aggravation for 2 days". One week before admission, the patient showed blood in sputum without inducement, bright red color, small amount, 1 to 2 times/d, no chest pain, and no treatment. Hemoptysis began to occur 2 days ago, bright red or dark red in color, mixed with blood clots, 3~10 times a day, no dysphagia, no hot flashes and night sweats, came to our hospital for treatment, lung CT showed "multiple nodular shadows in both lungs, pericardial effusion" (Figure 1), was admitted for further diagnosis and treatment. There was no significant weight gain or loss since the onset of the disease. He had "bronchial asthma" when he was young, but he did not attack in adulthood. Has a history of "hypertension" and is currently treated with oral "indapamide"; He claimed to have "history of metallurgical tours" and "history of contact with raw poultry", and had no history of allergies and tobacco and alcohol habits.

A 43-year-old male went to the Second Affiliated Hospital of Zhejiang University School of Medicine on November 7, 2013 because he found a painless mass behind his left ear for 3 years and increased by half a year. Physical examination: A soft mass was palpable behind the left ear, with clear borders, no tenderness, and movable. Considering a benign tumor of the parotid gland, parotid mass resection was performed under general anesthesia on November 15, 2013.

The proband was a 36-year-old male, tall and thin, 1.95 m tall, with aortic dilatation, having undergone aortic valve replacement surgery, ocular lens subluxation, and the clinical diagnosis was Marfan syndrome (MFS, MIM#154700); The daughter of the proband, 6 and a half years old, was tall and thin, 1.43 m tall, with slender fingers and no abnormalities in the eyes and heart. The family patients were all from Hebei Province, China (Figure 1)。 Because the proband couple was pregnant and wanted to give birth again, they came to the prenatal diagnosis center of the First Affiliated Hospital of Zhengzhou University for treatment. High-throughput sequencing of the proband (Ⅰ:1) was performed at BGI using an exon capture chip, and the MFS pathogenic gene fibrillin-1 (FBN1) was selected for detection, and three mutations were found (Table 1)。 The mutation of c. 8569G>T (p. Glu2857Ter) was found to be a suspected pathogenic mutation by comparison analysis of dbSNP137 database, 1 000 genome database and 200 healthy people control local database, and high-throughput sequencing sequence alignment of this mutation site was performed (Figure 2)。 A nonsense mutation c.8569G>T (p.Glu2857Ter) was detected in exon 65 of the FBN1 gene of the proband (I:1) in the Sanger sequencing verification family, which is heterozygous (Figure 3), consistent with the high-throughput sequencing detection results. This mutation causes glutamate at position 2857 to become a stop codon, causing the premature termination of FBN1 encoding, synthesizing a truncated protein, which may affect protein function. Sanger sequencing found that the daughter of the proband in the family (Ⅱ:1) carried the pathogenic mutation c.8569G>T (p.Glu2857Ter) and was genetically diagnosed as a patient with MFS. The wife of the proband in the family (Ⅰ:2) did not have this mutation (Figure 3)。 After identifying the pathogenic mutation c.8569G>T (p.Glu2857Ter) in this family, the proband's wife underwent prenatal diagnosis at 11 weeks of pregnancy, and Sanger sequencing found that there was a nonsense mutation c.8569G>T (p.Glu2857Ter) in exon 65 of FBN1 gene in the fetus (Ⅱ:2) (Figure 3)。 The pregnant women and their families were informed that the fetus carried the pathogenic nonsense mutation c.8569G>T (p.Glu2857Ter), which was more likely to be a patient with MFS after birth. The pregnant women and their families chose to terminate the pregnancy. The results of DNA analysis of abortus showed that the fetus carried the nonsense mutation c.8569G>T (p.Glu2857Ter), which was consistent with the results of prenatal diagnosis.