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Clear cell renal cell carcinoma (ccRCC) is the most common histological type of renal carcinoma and has a high recurrence rate and poor outcome. Accurate patient risk stratification based on genetic markers can help to identify the high-risk patient for early and further treatments and would promote patient survival. Long non-coding RNAs (lncRNAs) have attracted widespread attention as biomarkers for early diagnosis, treatment, and prognosis because of their high specificity and sensitivity. Here, we performed a systematic search in NCBI PubMed and found 44 lncRNAs as oncogenes, 18 lncRNAs as tumor suppressors, 199 lncRNAs as diagnostic biomarkers, 62 lncRNAs as prognostic biomarkers, and 3 lncRNAs as predictive biomarkers for ccRCC. We also comprehensively discuss the biological functions and molecular regulatory mechanisms of lncRNAs in ccRCC. Overall, the present study is a systemic analysis to assess the expression and clinical value of lncRNAs in ccRCC, and lncRNAs hold promise to be diagnostic, prognostic, and predictive biomarkers., Graphical abstract, lncRNAs play important roles in ccRCC. Here, Chao et al. write a systematic review to summarize and discuss the mechanisms, abnormal expressions, and clinical applications of lncRNAs in ccRCC, which provides a comprehensive insight into the research field of molecular regulatory mechanisms of lncRNAs in ccRCC.

Autophagy can protect cells and organisms from stressors such as nutrient deprivation, and is involved in many pathological processes including human cancer. Therefore, it is necessary to investigate the role of autophagy-related genes (ARGs) in cancer. In this study, we investigated the gene expression of 222 ARGs in 1048 Kidney Renal Clear Cell Carcinoma (KIRC) cases, from 5 independent cohorts. The gene expression of ARGs were first evaluated in the The Cancer Genome Atlas (TCGA) by Recevier Operating Characteristic (ROC) analysis to select potential biomarkers with extremely high ability in KIRC detection (AUC≥0.85 and p

Gene expression profiling data with long-term clinical follow-up information are great resources to screen, develop, evaluate and validate prognostic biomarkers in translational cancer research. However, an easy-to-use interactive online tool is needed to analyze these profiling and clinical data. In the current work, we developed OSacc (Online consensus Survival analysis of ACC), a web tool that provides rapid and user-friendly survival analysis based on seven independent transcriptomic profiles with long-term clinical follow-up information of 259 ACC patients gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. OSacc allows researchers and clinicians to evaluate the prognostic value of genes of interest by Kaplan-Meier (KM) survival plot with hazard ratio (HR) and log-rank test in ACC. OSacc is freely available at http://bioinfo.henu.edu.cn/ACC/ACCList.jsp.

Vaccinations are widely credited with reducing death rates from COVID-19 but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammation, non-cardiogenic edema, and hyaline membrane formation. Because proteostatic pathways play central roles in cellular protection, immune modulation, protein degradation and tissue repair, we examined the pathological features for the unfolded protein response (UPR) using the surrogate biomarker glucose regulated protein 78 (GRP78) and co-receptor for SARS-CoV-2. At autopsy, immunostaining of COVID-19 lungs showed highly elevated expression of GRP78 in both pneumocytes and macrophages compared to non-COVID control lungs. GRP78 expression was detected in both SARS-CoV-2 infected and un-infected pneumocytes as determined by multiplexed immunostaining for nucleocapsid protein. In macrophages, immunohistochemical staining for GRP78 from deceased COVID-19 patients was increased but overlapped with GRP78 expression taken from surgical resections of non-COVID-19 controls. In contrast, the robust in situ GRP78 immunostaining of pneumocytes from COVID-19 autopsies exhibited no overlap and was independent of age, race/ethnicity and gender compared with non-COVID-19 controls. Our findings bring new insights for stress-response pathways involving the proteostatic network implicated for host resilience and suggest that targeting of GRP78 expression might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.

Human coronavirus disease 2019 (COVID-19) is a life-threatening and highly contagious disease caused by coronavirus SARS-CoV-2. Sensitive and specific detection of SARS-CoV-2 virus in tissues and cells of COVID-19 patients will support investigations of the biologic behavior and tissue and cell tropism of this virus. We identified two commercially available affinity-purified polyclonal antibodies raised against Nucleocapsid and Spike proteins of SARS-CoV-2 that provide sensitive and specific detection of the virus by immunohistochemistry in formalin-fixed, paraffin-embedded tissue. Protocols are presented that are mutually validated by matched detection patterns of virus-infected cells in autopsy lung tissue of COVID-19 deceased patients by the two distinctly different antibodies. Negative controls include autopsy lung tissue from patient who died from non-COVID-19 respiratory disease and control rabbit immunoglobulin. SARS-CoV-2 detection in human tissues will provide insights into viral tissue and cell distribution and load in patients with active infection as well as provide insight into clearance of virus in late COVID-19 disease stages.

Land use change is the second largest source of greenhouse gas emissions after fossil combustion, which can hurt ecological environment severely. Intensive study on land use carbon emissions is of great significance to alleviate environmental pressure, formulate carbon emission reduction policy, and protect ecological development. The lower Yellow River area is an important area of economic development, grain cultivation, and agricultural production in China. Land use change has significant economic, environmental, and ecological impacts in this region. Deep study of land used carbon emissions and its influencing factors in the lower Yellow River area is not only of great significance to the environmental improvement in the Yellow River basin, but also can provide references for the research of other basins. Based on this, this paper studies the land use carbon emissions of 20 cities in the lower Yellow River area from 1995 to 2018. The results showed that from 1995 to 2018, the land use change was characterized by the decrease of the ecological land and the increase of the built-up land significantly. The overall carbon emission of the lower Yellow River area is increasing, and the built-up land is the main factor that leads to the increase of carbon emission, which can be also proven by the analysis of the Stochastic Impacts by Regression on Population, Affluence, and Technology (STIRPAT) model. The economic contributive coefficient (ECC) and ecological support coefficient (ESC) of carbon emission in the lower Yellow River area show a trend of high in Zhengzhou, Jinan, and Zibo and low in Zhoukou, Shangqiu, and Heze, and there was no significant changes during the study period, which indicates that each city did not achieve the coordinated development of the ecological economy. Finally, analysis results of the STIRPAT model indicated that the area of built-up land had the greatest impact on land use carbon emissions, followed by tertiary industry, whereas per capita gross domestic product (GDP) had the smallest impact. For every 1% increase in the area of built-up land, carbon emissions increased by 1.024%. By contrast, for every 1% increase in the contribution of tertiary industry to the GDP and per capita GDP, carbon emissions decreased by 0.051% and 0.034%, respectively. According to the study, there are still many problems in the coordinated development of economy and ecology in the lower Yellow River area. The lower Yellow River area should control the expansion of built-up land, afforestation, development of technology, reduction of carbon emissions, and promotion of the high-quality development of the Yellow River Basin.

OBJECTIVES: Assess the pathologic changes in the lungs of COVID-19 decedents and correlate these changes with demographic data, clinical course, therapies, and duration of illness. METHODS: Lungs of 12 consecutive COVID-19 decedents consented for autopsy were evaluated for gross and histopathologic abnormalities. A complete Ghon "en block" dissection was performed on all cases; lung weights and gross characteristics recorded. Immunohistochemical studies were performed to characterize lymphocytic infiltrates and to assess SARS-CoV-2 capsid protein. RESULTS: Two distinct patterns of pulmonary involvement were identified. Three of 12 cases demonstrated a predominance of acute alveolar damage (DAD) while 9 of 12 cases demonstrated a marked increase in intra-alveolar macrophages in a fashion resembling desquamative interstitial pneumonia or macrophage activation syndrome (DIP/MAS). Two patterns were correlated solely with a statistically significant difference in the duration of illness. The group exhibiting DAD had duration of illness of 5.7 days while the group with DIP/MAS had duration of illness of 21.5 days (t-test p = 0.014). CONCLUSIONS: The pulmonary pathology of COVID-19 patients demonstrates a biphasic pattern, an acute phase demonstrating DAD changes while the patients with a more prolonged course exhibit a different pattern that resembles DIP/MAS-like pattern. The potential mechanisms and clinical significance are discussed.

Human coronavirus disease 2019 (COVID-19) is a life-threatening and highly contagious disease caused by coronavirus SARS-CoV-2. Sensitive and specific detection of SARS-CoV-2 viral proteins in tissues and cells of COVID-19 patients will support investigations of the biologic behavior and tissue and cell tropism of this virus. We identified commercially available affinity-purified polyclonal antibodies raised against nucleocapsid and spike proteins of SARS-CoV-2 that provide sensitive and specific detection of the virus by immunohistochemistry in formalin-fixed, paraffin-embedded tissue. Two immunohistochemistry protocols are presented that are mutually validated by the matched detection patterns of the two distinct viral antigens in virus-infected cells within autopsy lung tissue of COVID-19 deceased patients. Levels of nucleocapsid protein in the lungs of COVID-19 decedents, as measured by quantitative histo-cytometry of immunohistochemistry images, showed an excellent log–linear relationship with levels of viral nucleocapsid RNA levels, as measured by qRT-PCR. Importantly, since the nucleocapsid protein sequence is conserved across all known viral strains, the nucleocapsid immunohistochemistry protocol is expected to recognize all common variants of SARS-CoV-2. Negative controls include autopsy lung tissues from patients who died from non-COVID-19 respiratory disease and control rabbit immunoglobulin. Sensitive detection of SARS-CoV-2 in human tissues will provide insights into viral tissue and cell distribution and load in patients with active infection, as well as provide insight into the clearance rate of virus in later COVID-19 disease stages. The protocols are also expected to be readily transferable to detect SARS-CoV-2 proteins in tissues of experimental animal models or animals suspected to serve as viral reservoirs.

Autophagy can protect cells and organisms from stressors such as nutrient deprivation, and is involved in many pathological processes including human cancer. Therefore, it is necessary to investigate the role of autophagy-related genes (ARGs) in cancer. In this study, we investigated the gene expression of 222 ARGs in 1048 Kidney Renal Clear Cell Carcinoma (KIRC) cases, from 5 independent cohorts. The gene expression of ARGs were first evaluated in the The Cancer Genome Atlas (TCGA) by Recevier Operating Characteristic (ROC) analysis to select potential biomarkers with extremely high ability in KIRC detection (AUC≥0.85 and p

Uveal melanoma (UM) is a rare, aggressive, but the most frequent primary intraocular malignancy in adults, and up to 50% of patients develop a tendency of liver metastases. Great efforts have been made to develop biomarkers that facilitate diagnosis, prediction of the risk, and response to treatment of UM. However, a biologically informative and highly accurate gold standard system for prognostic evaluation of UM remains to be established. To facilitate assessment of the prognosis of UM patients, we established a user-friendly Online consensus Survival tool for uveal melanoma, named OSuvm, by which users can easily estimate the prognostic values of genes of interest by the Kaplan-Meier survival plot with hazard ratio and log-rank test. OSuvm comprises four independent cohorts including 229 patients with both gene expression profiles and relevant clinical follow-up information, and it has shown great performance in evaluating the prognostic roles of previously reported biomarkers. Using OSuvm enables researchers and clinicians to rapidly and conveniently explore the prognostic value of genes of interest and develop new potential molecular biomarkers for UM. OSuvm can be accessed at http://bioinfo.henu.edu.cn/UVM/UVMList.jsp.

Aim: To develop a free and quick analysis online tool that allows users to easily investigate the prognostic potencies of interesting genes in kidney renal clear cell carcinoma (KIRC). Patients & methods: A total of 629 KIRC cases with gene expression profiling data and clinical follow-up information are collected from public Gene Expression Omnibus and The Cancer Genome Atlas databases. Results: One web application called Online consensus Survival analysis for KIRC (OSkirc) that can be used for exploring the prognostic implications of interesting genes in KIRC was constructed. By OSkirc, users could simply input the gene symbol to receive the Kaplan–Meier survival plot with hazard ratio and log-rank p-value. Conclusion: OSkirc is extremely valuable for basic and translational researchers to screen and validate the prognostic potencies of genes for KIRC, publicly accessible at http://bioinfo.henu.edu.cn/KIRC/KIRCList.jsp

Gene expression profiling data with long-term clinical follow-up information are great resources to screen, develop, evaluate and validate prognostic biomarkers in translational cancer research. However, an easy-to-use interactive online tool is needed to analyze these profiling and clinical data. In the current work, we developed OSacc (Online consensus Survival analysis of ACC), a web tool that provides rapid and user-friendly survival analysis based on seven independent transcriptomic profiles with long-term clinical follow-up information of 259 ACC patients gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. OSacc allows researchers and clinicians to evaluate the prognostic value of genes of interest by Kaplan–Meier (KM) survival plot with hazard ratio (HR) and log-rank test in ACC. OSacc is freely available at http://bioinfo.henu.edu.cn/ACC/ACCList.jsp.

The present study reports the clinical data of two patients with renal pelvis carcinoma and one patient with renal carcinoma who developed port-site metastasis following retroperitoneal laparoscopic surgery. The current study aimed to identify the cause and prognosis of the occurrence of port-site metastasis subsequent to laparoscopic radical resection of renal pelvis carcinoma and nephron-sparing surgery. Post-operative pathology confirmed the presence of high-grade urothelial cell carcinoma in two patients and Fuhrman grade 3 renal clear cell carcinoma in one patient. Port-site metastasis was initially detected 1-7 months post-surgery. The two patients with renal pelvis carcinoma succumbed to the disease 2 and 4 months following the identification of the port-site metastasis, respectively, whereas the patient with renal carcinoma survived with no disease progression during the targeted therapy period. The occurrence of port-site metastasis may be attributed to systemic and local factors. Measures to reduce the development of this complication include strict compliance with the operating guidelines for tumor surgery, avoidance of air leakage at the port-site, complete removal of the specimen with an impermeable bag, irrigation of the laparoscopic instruments and incisional wound with povidone-iodine when necessary, and enhancement of the body's immunity. Close post-operative follow-up observation for signs of recurrence or metastasis is essential, and systemic chemotherapy may be required in patients with high-grade renal pelvis carcinoma and renal carcinoma in order to prolong life expectancy.

This work demonstrated that a cold-induced DEAD-box RNA helicase, CbDRH, is also post-transcriptionally regulated upon cold stress, and it interacts with a cold-responsive, glycine-rich, RNA-binding protein, CbGRP. Chorispora bungeana (C. bungeana) is a representative alpine subnival plant species that shows strong tolerance to multiple abiotic stresses, especially cold stress. DEAD-box RNA helicases are implicated in almost all RNA metabolic processes and participate in multiple abiotic stress responses. Here, we characterized a cold-induced DEAD-box RNA helicase gene from C. bungeana. We cloned the full-length cDNA of the gene by RACE and called it C. bungeana DEAD-box RNA Helicase (CbDRH). Structurally, CbDRH possesses all nine conserved motifs characteristic of DEAD-box protein family members in its central region, and the N- and C- terminal extensions both harbor a glycine-rich region containing several RGG-box motifs. The CbDRH gene produces two forms of transcripts, CbDRH.2 and CbDRH.1, by alternative splicing. CbDRH.2 comes from the complete excision of all the nine introns, while CbDRH.1 results from the use of an alternative 5′ splice site in the eighth intron, retaining part of the intron (the first 260 bp) with an early stop codon. Semi-quantitative RT-PCR analysis showed that CbDRH.2, but not CbDRH.1, is up-regulated by cold stress. However, the abundance of CbDRH.1 transcript can be elevated by cycloheximide (an inhibitor of nonsense-mediated decay) treatment, indicating that CbDRH.1 is targeted to nonsense-mediated decay (NMD). A subcellular localization analysis showed that CbDRH.2 protein is located in the nuclei. Further investigation suggested that CbDRH.2 can interact with a cold-responsive, glycine-rich, RNA-binding protein, CbGRP (Chorispora bungeana glycine-rich, RNA-binding protein). These data suggest that the cold-induced CbDRH is also post-transcriptionally regulated under cold stress and that CbDRH.2 may function together with the glycine-rich, RNA-binding protein, CbGRP, in the cold stress response.

The neonatal Fc receptor (FcRn) is a major regulator of IgG and albumin homeostasis systemically and in the kidneys. We investigated the role of FcRn in the development of immune complex-mediated glomerular disease in mice. C57Bl/6 mice immunized with the noncollagenous domain of the α3 chain of type IV collagen (α3NC1) developed albuminuria associated with granular capillary loop deposition of exogenous antigen, mouse IgG, C3 and C5b-9, and podocyte injury. High-resolution imaging showed abundant IgG deposition in the expanded glomerular basement membrane, especially in regions corresponding to subepithelial electron dense deposits. FcRn-null and -humanized mice immunized with α3NC1 developed no albuminuria and had lower levels of serum IgG anti-α3NC1 antibodies and reduced glomerular deposition of IgG, antigen, and complement. Our results show that FcRn promotes the formation of subepithelial immune complexes and subsequent glomerular pathology leading to proteinuria, potentially by maintaining higher serum levels of pathogenic IgG antibodies. Therefore, reducing pathogenic IgG levels by pharmacologic inhibition of FcRn may provide a novel approach for the treatment of immune complex-mediated glomerular diseases. As proof of concept, we showed that a peptide inhibiting the interaction between human FcRn and human IgG accelerated the degradation of human IgG anti-α3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG.

Goodpasture disease is an autoimmune kidney disease mediated by autoantibodies against noncollagenous domain 1 (NC1) monomers of α3(IV) collagen that bind to the glomerular basement membrane (GBM), usually causing rapidly progressive glomerulonephritis (GN). We identified a novel type of human IgG4-restricted anti–GBM autoantibodies associated with mild nonprogressive GN, which specifically targeted α345NC1 hexamers but not α3NC1 monomers. The mechanisms eliciting these anti–GBM autoantibodies were investigated in mouse models recapitulating this phenotype. Wild-type and FcγRIIB−/− mice immunized with autologous murine GBM NC1 hexamers produced mouse IgG1-restricted autoantibodies specific for α345NC1 hexamers, which bound to the GBM in vivo but did not cause GN. In these mice, intact collagen IV from murine GBM was not immunogenic. However, in Col4a3−/− Alport mice, both intact collagen IV and NC1 hexamers from murine GBM elicited IgG Abs specific for α345NC1 hexamers, which were not subclass restricted. As heterologous Ag in COL4A3-humanized mice, murine GBM NC1 hexamers elicited mouse IgG1, IgG2a, and IgG2b autoantibodies specific for α345NC1 hexamers and induced anti–GBM Ab GN. These findings indicate that tolerance toward autologous intact α345(IV) collagen is established in hosts expressing this Ag, even though autoreactive B cells specific for α345NC1 hexamers are not purged from their repertoire. Proteolysis selectively breaches this tolerance by generating autoimmunogenic α345NC1 hexamers. This provides a mechanism eliciting autoantibodies specific for α345NC1 hexamers, which are restricted to noninflammatory IgG subclasses and are nonnephritogenic. In Alport syndrome, lack of tolerance toward α345(IV) collagen promotes production of alloantibodies to α345NC1 hexamers, including proinflammatory IgG subclasses that mediate posttransplant anti–GBM nephritis.

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and a significant cause of end-stage renal disease, yet current therapies are nonspecific, toxic, and often ineffective. The development of novel targeted therapies requires a detailed understanding of the pathogenic mechanisms, but progress is hampered by the lack of a robust mouse model of disease. We report that DBA/1 mice as well as congenic FcγRIII−/− and FcRγ−/− mice immunized with a fragment of α3(IV) collagen developed massive albuminuria and nephrotic syndrome, because of subepithelial deposits of mouse IgG and C3 with corresponding basement membrane reaction and podocyte foot process effacement. The clinical presentation and histopathologic findings were characteristic of MN. Although immunized mice produced genuine anti-α3NC1 autoantibodies that bound to kidney and lung basement membranes, neither crescentic glomerulonephritis nor alveolitis ensued, likely because of the predominance of mouse IgG1 over IgG2a and IgG2b autoantibodies. The ablation of activating IgG Fc receptors did not ameliorate injury, implicating subepithelial deposition of immune complexes and consequent complement activation as a major effector pathway. We have thus established an active model of murine MN. This model, leveraged by the availability of genetically engineered mice and mouse-specific reagents, will be instrumental in studying the pathogenesis of MN and evaluating the efficacy of novel experimental therapies.

NMDA receptors are found in neurons both at synapses and in extrasynaptic locations. Extrasynaptic locations are poorly characterized. Here we used preembedding immunoperoxidase and postembedding immunogold electron microscopy and fluorescence light microscopy to characterize extrasynaptic NMDA receptor locations in dissociated hippocampal neurons in vitro and in the adult and postnatal hippocampus in vivo. We found that extrasynaptic NMDA receptors on neurons in vivo and in vitro were usually concentrated at points of contact with adjacent processes, which were mainly axons, axon terminals, or glia. Many of these contacts were shown to contain adhesion factors such as cadherin and catenin. We also found associations of extrasynaptic NMDA receptors with the membrane associated guanylate kinase (MAGUKs), postsynaptic density (PSD)-95 and SAP102. Developmental differences were also observed. At postnatal day 2 in vivo, extrasynaptic NMDA receptors could often be found at sites with distinct densities whereas dense material was seen only rarely at sites of extrasynaptic NMDA receptors in the adult hippocampus in vivo. This difference probably indicates that many sites of extrasynaptic NMDA receptors in early postnatal ages represent synapse formation or possibly sites for synapse elimination. At all ages, as suggested in both in vivo and in vitro studies, extrasynaptic NMDA receptors on dendrites or the sides of spines may form complexes with other proteins, in many cases, at stable associations with adjacent cell processes. These associations may facilitate unique functions for extrasynaptic NMDA receptors.

Background and Purpose— Blockade of angiotensin II AT 1 receptors in cerebral microvessels protects against brain ischemia and inflammation. In this study, we tried to clarify the presence and regulation of the local renin-angiotensin system (RAS) in brain microvessels in hypertension. Methods— Spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) controls were treated with an AT 1 receptor antagonist (candesartan, 0.3 mg/kg per day) via subcutaneous osmotic minipumps for 4 weeks. The expression and localization of RAS components and the effect of AT 1 receptor blockade were assessed by Affymetrix microarray, qRT-PCR, Western blots, immunohistochemistry and immunofluorescence. Results— We found transcripts of most of RAS components in our microarray database, and confirmed their expression by qRT-PCR. Angiotensinogen (Aogen), angiotensin-converting enzyme (ACE) and AT 1 receptors were localized to the endothelium. There was no evidence of AT 2 receptor localization in the microvascular endothelium. In SHR, (pro)renin receptor mRNA and AT 1 receptor mRNA and protein expression were higher, whereas Aogen, ACE mRNA and AT 2 receptor mRNA and protein expression were lower than in WKY rats. Candesartan treatment increased Aogen, ACE and AT 2 receptor in SHR, and increased ACE and decreased Aogen in WKY rats, without affecting the (pro)renin and AT 1 receptors. Conclusions— Increased (pro)renin and AT 1 receptor expression in SHR substantiates the importance of the local RAS overdrive in the cerebrovascular pathophysiology in hypertension. AT 1 receptor blockade and increased AT 2 receptor stimulation after administration of candesartan may contribute to the protection against brain ischemia and inflammation.

Supplemental Digital Content is available in the text, Background: Pancreatic cancer (PC) is one of the most lethal digestive system tumors. Most new cases are diagnosed based on metastasis or local aggression and are known as “advanced PC.” Recently, studies investigating S-1 have indicated that it has a better clinical curative effect on PC. We conducted a meta-analysis to evaluate the efficacy and safety of S-1 monotherapy compared with S-1 combination regimens in patients with gemcitabine (GEM)-refractory PC. Methods: Trials published between 1978 and 2016 were identified by an electronic search of public databases (Medline, Embase, and the Cochrane Library). All prospective studies were independently identified by 2 authors for inclusion. The response rate (RR), progression-free and overall survival (PFS and OS, respectively), and the primary toxicities were extracted for the meta-analysis. Results: Four randomized controlled trials consisting of 623 patients were included in the analysis, among which 315 patients underwent S-1 monotherapy and 308 patients underwent S-1 combination therapy. The pooled data showed a significantly higher response rate and longer PFS in the S-1 combination group than in the S-1 monotherapy group (RR, 1.75; 95% confidence interval [CI], 1.19–2.57; P = .005 and hazard ration [HR], 0.75; 95% CI, 0.62–0.91; P = .005). There were no significant differences in OS or adverse events. Conclusions: Compared with the S-1 monotherapy group, the S-1 combination group had a higher response rate and longer PFS. Both groups had few adverse events, which were balanced between the groups. The subgroup analysis suggested that S-1 combination regimens with leucovorin or irinotecan (CPT-11) provided promising efficacy. These promising combination regimens should be considered for patients with advanced PC who choose S-1 as their second-line therapy.

A critical review was conducted of studies of work-related low back pain in the People's Republic of China. The published literature in both the English and Chinese languages from 1983 to 1997 was reviewed for studies that permitted the calculation of prevalence ratios. Thirty-five papers were identified initially, and after quality inclusion/exclusion criteria were applied, 16 (14 in Chinese and two in English) were selected for more detailed review. Prevalence ratios were statistically elevated in all but two of the selected studies. Prevalence ratios for individual groups ranged from 2.0 to 8.5 for bending and twisting, 1.5 to 14.3 for static posture, 1.9 to 5.5 for whole-body vibration, and 2.6 to 9.4 for low-temperature exposure. The literature was limited by the absence of standardized and robust measures of low-back-pain outcomes and exposures and by the omission of fundamental details from research reports. Even with these limitations, the review findings suggest that three physical risk factors, all well known in the international literature, are associated with the prevalence of low back pain in the People's Republic of China.

Alport post-transplant nephritis (APTN) is an aggressive form of anti-glomerular basement membrane disease that targets the allograft in transplanted patients with X-linked Alport syndrome. Alloantibodies develop against the NC1 domain of α5(IV) collagen, which occurs in normal kidneys, including renal allografts, forming distinct α345(IV) and α1256(IV) networks. Here, we studied the roles of these networks as antigens inciting alloimmunity and as targets of nephritogenic alloantibodies in APTN. We found that patients with APTN, but not those without nephritis, produce two kinds of alloantibodies against allogeneic collagen IV. Some alloantibodies targeted alloepitopes within α5NC1 monomers, shared by α345NC1 and α1256NC1 hexamers. Other alloantibodies specifically targeted alloepitopes that depended on the quaternary structure of α345NC1 hexamers. In Col4a5-null mice, immunization with native forms of allogeneic collagen IV exclusively elicited antibodies to quaternary α345NC1 alloepitopes, whereas alloimmunogens lacking native quaternary structure elicited antibodies to shared α5NC1 alloepitopes. These results imply that quaternary epitopes within α345NC1 hexamers may initiate alloimmune responses after transplant in X-linked Alport patients. Thus, α345NC1 hexamers are the culprit alloantigen and primary target of all alloantibodies mediating APTN, whereas α1256NC1 hexamers become secondary targets of anti-α5NC1 alloantibodies. Reliable detection of alloantibodies by immunoassays using α345NC1 hexamers may improve outcomes by facilitating early, accurate diagnosis.