Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine tumor with unique characteristics, and its treatment regimens are primarily derived from those for small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In recent years, the incidence rate has been on the rise, and the prognosis are affected by the interaction of multiple factors such as individual, clinical stage and treatment mode, and the heterogeneity is significant. In the study of molecular subtypes, multiple subgroups were divided according to key gene mutations such as RB1 and TP53, and genomic subtypes were associated with survival, chemotherapy response, and efficacy of precision therapy. Targeted therapy excavates multiple targets, and the efficacy of drugs is different. Immunotherapy has made remarkable progress, and immune checkpoint inhibitors (ICIs) have been effective in all stages of chemotherapy alone or in combination with chemotherapy or radiation therapy, but there is a risk of hyperprogressive diseases, and accurate prognostic markers need to be explored urgently. This review reviews the latest research progress in the study of molecular subtypes and precision therapies such as targeted therapy and immunotherapy of pulmonary LCNEC, and points out that pulmonary LCNEC treatment will develop in the direction of precision and individualization in the future.
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Humans ; Lung Neoplasms/drug therapy* ; Carcinoma, Neuroendocrine/drug therapy* ; Precision Medicine ; Immunotherapy ; Carcinoma, Large Cell/drug therapy*

TROP-2, a tumor-associated antigen, has been implicated in the progression of various epithelial tumors. Due to its favorable expression profile, TROP-2 has emerged as a promising target for antibody-drug conjugates (ADCs) based anti-tumor therapies. Although ADCs have shown efficacy in cancer treatment, their application in solid tumors is hindered by their high molecular weight, poor tumor penetration, and release of cytotoxic molecules. Therefore, a recombinant immunotoxin was developed based on a shark-derived variable domain of immunoglobulin new antigen receptor (VNAR) antibody. VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability. In this study, a shark VNAR phage display library was created, leading to the identification of shark VNAR-5G8 that targets TROP-2. VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2. Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2. Subsequently, VNAR-5G8 was fused with a truncated form of Pseudomonas exotoxin (PE38) to create the recombinant immunotoxin (5G8-PE38), which exhibited significant anti-tumor activity in vitro and in vivo. Overall, this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy.

Objective To investigate the combined effect of noise and hand-transmitted vibration on hearing loss in male noise-exposed workers. Methods A total of 952 male noise-exposed workers from an automobile manufacturing enterprise were selected as the research subjects using judgment sampling method. Occupational epidemiological surveys, assessments of occupational hazards in workplace, and pure-tone audiometry tests were conducted on the research subjects, and they were divided into low-level noise group, low-level combined group, high-level noise group, and high-level combined group according to whether the noise exposure level exceeded the national standard and whether they were jointly exposed to hand-transmitted vibration. The joint effects of noise and hand-transmitted vibration on hearing loss were analyzed. Results The detection rate of hearing loss in 952 noise-exposed workers was 21.7%. The detection rate of hearing loss of four groups, from high to low, was as follows： high-level combined group, high-level noise group, low-level combined group, and low-level noise group (44.9% vs 32.7% vs 12.9% vs 5.7%, P<0.01). The results of multivariate logistic regression analysis showed that the risk of hearing loss in the low-level noise group, the low-level combined group, the high-level noise group and the high-level combined group increased sequentially after adjusting for the confounding factors such as age, education level, smoking, drinking, listening to music with headphones, frequency of wearing noise-blocking earplugs and body mass index. The risk of hearing loss in the high-level noise group was 8.62 times more than that of the low-level noise group (P<0.01). The risk of hearing loss in the low-level noise combined group was 2.50 times more than that of the low-level noise group (P<0.01). The risks of hearing loss in the high-level combined group were 5.76 and 1.67 times more than that of the low-level combined group and the high-level noise group. Conclusion Combined exposure to noise and hand-transmitted vibration can increase the risk of hearing loss in male noise-exposed workers, and the higher the noise intensity, the greater the synergistic effect. Hand-transmitted vibration is a synergistic risk factor for occupational noise-induced hearing loss.

{L-End}Objective To analyze the prevalence of multi-site work-related musculoskeletal disorders (WMSDs) and their influencing factors among workers in the chemical pharmaceutical industry. {L-End}Methods A total of 563 workers from three chemical pharmaceutical factories in Guangzhou City were selected as the research subjects using the judgment sampling method. The prevalence of multi-site WMSDs in the past 12 months was investigated using the electronic questionnaire of Chinese Version of Musculoskeletal Disorders Questionnaire. {L-End}Results The prevalence of multi-site WMSDs in the research subjects was 30.0% (169/563). The results of multivariable logistic regression analysis showed that workers who smoked regularly/frequently and those who had their hands above shoulder level for long periods of time had a lower risk of multi-site WMSDs than those who never/occasionally smoked (all P≤0.05). Workers with a high school, secondary specialty, college degree, or above had a lower risk of multi-site WMSDs than those with a middle school education or below (all P<0.05). The longer the daily working hours, the higher the risk of multiple WMSDs (all P<0.05). Workers with regular/frequently work shifts had a lower risk of multi-site WMSDs than those with none/occasional work shifts (P<0.05). {L-End}Conclusion The prevalence of multi-site WMSDs among workers in the chemical pharmaceutical industry is relatively high. The influencing factors are individual factors, unreasonable work organization and poor ergonomics factors.

Objective:To investigate the spectrum of amino acid, organic acid, and fatty acid oxidative metabolic diseases in children diagnosed by detecting urinary organic acid levels using gas chromatography-mass spectrometry.Methods:From January 2005 to December 2021, clinical data of 2 461 children diagnosed with inherited metabolic diseases (IMD) by gas chromatography-mass spectrometry, in combination with tandem mass spectrometry and genetic testing in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were retrospectively analyzed.Results:Among 2 461 children, 1 446 were male and 1 051 were female. A total of 32 types of IMD were detected among 2 461 patients, which included 10 amino acid disorders in 662 cases (26.9%), 6 common diseases were hyperphenylalaninemia, citrin deficiency, ornithine carbamoyltransferase deficiency, maple syrup urine disease, alkaptonuria, and tyrosinemia-I, 17 types of organic acidemias in 1 683 cases (68.4%), 6 common diseases were methylmalonic acidemia, propionic acidemia, valeric acidemia-type Ⅰ, isovaleric acidemia, 3-methylcrotonyl-CoA carboxylase deficiency and multiple carboxylase deficiency and 5 fatty acid β oxidative defects in 116 cases (4.7%), 2 common diseases were multiple acyl-CoA dehydrogenase deficiency and short-chain acyl-CoA dehydrogenase deficiency).Conclusion:Among the diseases diagnosed by analyzing urinary organic acid profiling with gas chromatography-mass spectrometry, the most common are organic acidemias, followed by amino acid disorders and fatty acid oxidation defects.

Objective To retrospectively analyze and compare the clinical efficacy and safety between fractionated stereotactic radiotherapy (FSRT) combined with and without temozolomide in the treatment of large brain metastases.Methods Between 2009 and 2017,84 patients with large brain metastases (tumor size ≥ 6 cm3) were recruited and assigned into the CRT group (concurrent TMZ and FSRT,n=42) and RT group (FSRT alone,n=42).The radiation dose was 52.0 Gy in 13 fractions or 52.5 Gy in 15 fractions.Patients were reexamined by magnetic resonance imaging (MRI) during treatment.The radiation field would be shrunk if the gross target volume (GTV) was reduced.The clinical efficacy was evaluated at postoperative 2 to 3 months.The primary end-point event was local recurrence-free survival (LRFS) and the secondary end-point events included intracranial progression-free survival (IPFS),progression-free survival (PFS),overall survival (OS),brain metastasis-specific survival (BMSS) and adverse events.The survival rates were assessed with Kaplan-Meier method and log-rank test and monovariate analysis.Results The median GTV in the CRT and RT groups was 16.9 cm3 and 15.7 cm3.During the treatment,75％ of the lesions in the CRT group were reduced compared with 34％ in the RT group (P=0.000).The local control (LC) rate in the CRT and RT groups was 100％ and 98％.The median follow-up time was 16.1 months (range,2.1-105.7 months).In the CRT group,the LRFS (P=0.040),IPFS (P=0.022),PFS (P=0.045),OS (P=0.013) and BMSS (P=0.006) were significantly better than those in the RT group,respectively.In the CRT group,the incidence of grade Ⅰ-Ⅱ gastrointestinal adverse events was 33％,significantly higher compared with 26％ in the RT group (P=0.006).No grade Ⅳ-Ⅴ adverse events occurred in both groups.Conclusion Combined application of temozolomide and FSRT can further enhance the LC and survival rates and do not increase the risk of severe adverse events in patients diagnosed with large brain metastases.

Objective: To study the effect of sodium aescinate on the development process of lung injury induced by paraquat. Methods: Forty-five health adult male SD rats were randomly divided into control group, PQ group, sodium aescinate group, and 15 rats in each group. The PQ group and sodium aescinate group were given a one-time intraperitoneal injection of 18mg/kg body weight of rats PQ, the control group was given the same amout normal saline. Rats in sodium aescinate group were injected 2 mg/kg body weight sodium aescinate into abdominal cavity for 7 days continually, but the same volume of saline was injected into the other groups. Finally, at 7, 14 and 28 days after PQ poisoning, five rats were kills for measuring lung tissue pathological changes and the value of TGF-β₁, TNF-α, hydroxyproline in each group. Results: The expression of TNF-α in serum of 7th day [ (17.03±0.82) ng/ml] and 14th day [ (15.74±0.91) ng/ml] of sodium aescinate group were lower than the corresponding period of PQ groups’, and the difference had statistical significance (P<0.05) . The expression of TGF-β₁ in serum of 7th day[ (225.93±8.33) ng/ml], 14th day [ (216.62±9.48) ng/ml] and 28th[ (181.41±6.10) ng/ml] of sodium aescinate group were lower than the corresponding period of PQ groups’, and the difference had statistical significance (P<0.05) . Lung tissue pathological changes showed, compared with control group, inflammatory injury at 7th day and fibrosis degree at 28th of rats’ lung reduced on sodium aescinate group. The expression of hydroxyproline in rats’ lung of 7th day[ (1.246±0.018) μg/mg], 14th day [ (1.269±0.034) μg/mg] and 28th[ (1.283±0.028) μg/mg] of sodium aescinate group were lower than the corresponding period of PQ groups’, and the difference had statistical significance (P<0.05) . Conclusion sodium aescinate could reduce the pulmonary inflammatory injury and hydroxyproline value of PQ poisoning rats, so sodium aescinate could ameliorate lung injury induced by PQ.

Objective: To study the correlation of occupation musculoskeletal disease (OMD) and safety behavior in assembly line workers. Methods: Selected assembly line workers of 3 manufacturing factory in Pacity as the objects of this study by judgement sampling. Questionnaires were used for messages collection including the general sociodemographic characteristic, OMD condition, occupational safety behaviors. Results: This study shows that, 826 OMD workers were found that the annual prevalence was 38.03%. The scores of work posture, handling habits, health habit in OMD group was lower than non-OMD group (P<0.01) but personal protection behavior was higher than non-OMD group (P<0.01) . Test of binary logistic regression revealed that age, workage, work posture, handling habits were the factors of OMD (P<0.01) . Conclusion Safety behaviors were the potent factors of OMD that work posture and handling habits should be broadcast.

Objective: To observe the expression of integrin-linked kinase on pulmonary fibrosis of paraquat (PQ) poisoning rats, and to discuss the relationship between ILK with pulmonary fibrosis induced by paraquat. Methods: Forty male Sprague-Dawley (SD) rats were randomly divided into control group and paraquat group, 20 in each group; the PQ group rats were intraperitoneally injected PQ liquid (18 mg/kg) , and the control group rats were injected the same volume of saline; 5 rats of these two groups were respectively sacrificed after 7, 14, 28, 56 days of PQ injection; according to the results of lung biopsy HE staining and Masson staining to observe the lung pathologic changes, measure the value of lung hydroxyproline and the expression of ILK. Results: HE and Masson staining of lung pathological biopsy showed, the 7th day after PQ exposure lung tissue mostly had congestion, edema, inflammatory cells infiltration; the 14th inflammation reduced, fibrosis change appeared gradually; the 28th and 56th showed the lung tissue structure disorder and occurred apparent hydroproline with blue dye in pulmonary interstitium. Compared with control group in the same experiment period, the value of lung hydroxyproline in each experiment period of PQ group increased (P<0.05) , and the value of lung hydroxyproline of PQ group rose with the increasing of the time of PQ poisoning. The expression of ILK mRNA and protein in each experiment period of PQ group was higher than the control group in the same experiment period (P<0.05) ; ILK mRNA and protein of PQ group began to increase on 7 day phase, reached the highest on 28 day phase, and decreased on 56 day phase. Conclusion The expression of ILK mRNA and protein increased with the lung fibrosis progression of PQ poisoning rats, so ILK could be the key molecule target which induced pulmonary fibrosis of PQ poisoning.

OBJECTIVE: To examine the correlation between single nucleotide polymorphism( SNP) in 3' untranslated regions and hearing-related genes and their correlation with susceptibility in noise-induced hearing loss( NIHL) in Chinese Han population. METHODS: A total of 2 507 workers exposed to 72-120 d B( A) of normalized continuous A-weighted sound pressure level equivalent to a 40 h-working-week intensity of continuous noise in three large compressor manufacturing enterprises in Guangzhou were chosen as study subjects by judgment sampling method. A model was set up to define sensitive group( 238 sensitive workers) and resistant group( 238 resistant workers) by testing the workplace noise intensity and worker hearing pure tone threshold test. The genomic DNA from peripheral blood was collected from workers of these two groups. The genetic characteristic analysis was carried out by using the Taq Man probe with chemical fluorescence allelic identification test. RESULTS: The monaural threshold of weighted value( MTWV) of the left ear in sensitive group was higher than that of the right ear( P < 0. 01); the MTWV of left ear and right ear in sensitive group were respectively higher than that of the same ear in resistant group( P < 0. 01). A total of four candidate genes were screened: vesicle associated membrane protein 1( VAMP1),fibroblast growth factor 1( FGF1),potassium inwardly-rectifying channel,subfamily J,member 10( KCNJ10) and myosin IC( MYO1C). The results of SNP loci detection showed that more workers in sensitive group carried FGF1 rs17217562 AC and CC genotype than that of resistant group( P < 0. 05). More workers in sensitive group carried C allele of FGF1 rs17217562 than the resistant group( P < 0. 05). The logistic regression analysis showed that after correcting the confounding factors including age,noise exposure level,length of noise exposure,gender,smoking,drinking,whether or not using headset,organic solvents exposure,heavy metal exposure,high temperature exposure and hand-arm vibration exposure,the people carrying allele of FGF1 rs17217562 had an increased risk of NIHL susceptibility( P < 0. 05). The VAMP1,KCNJ10 and MYO1C gene had no susceptibility correlation with SNP and NIHL.CONCLUSION: Among Chinese Han population,SNP loci located on the FGF1 rs17217562 may be correlated with the susceptibility of NIHL.