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The provinces along the Silk Road Economic Belt in China section is undergoing a rapid economic development, but meanwhile poses a severe situation for the ecological environment. In this paper, we involved the pollution discharge account to analyse the pressure of natural capital depletion on the ecological environment from 2005 to 2016 with combination of improved ecological footprint and scissors difference. The results show that: (1) The ecological footprint (EF) in this region almost doubled over the past 12 years, while the ecological capacity (EC) was rather low and experienced a slightly decrease. With increase of ecological deficit (ED), the capital flow could not maintain economic and social development recently, and the depletion of the natural capital stock has become general. (2) Spatially, the variation of EF varies greatly in different provinces, but as a whole, the per capita EF in Northwest region was much higher than that in Southwest. The provinces with high EF depth concentrated in the east and north margin with relatively better economy, while the provinces with high EF size concentrated in northwest region with abundant resources and low population density. (3) The decrease of scissors difference between EF depth and EF size indicates that positive effects of ecological restoration projects have been exerted and the conflict between supply and demand of natural resources tends to be eased to some extent. These findings could provide specific policy implications for this region to improve the efficiency of natural capital utilization and promote the coordinated development of economy and environment.

Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have rapidly become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for treatment of melanoma, lung, renal cell, head and neck squamous, urothelial and increasing number of other solid and hematological malignancies. However, patients with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flare ups and worsening of pre-existing autoimmune disorders in patients with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to patients with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis and others autoimmune disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in patients with autoimmune diseases and advanced or metastatic solid tumors. The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in patients with autoimmune disorders and advanced or metastatic solid tumors. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced or metastatic solid tumors in which ICI are approved or have shown clinical activity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Key overall exclusion criteria include prior therapy with an anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 patients will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities defined for each autoimmune disease-specific cohort, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is currently enrolling patients in the participating sites through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345. Citation Format: Ecaterina E. Ileana Dumbrava, Maria Suarez-Almazor, Jeane Painter, Tanner M. Johanns, Michael L. Dougan, Laura Cappelli, Yinghong Wang, Clifton Bingham, Sarthak Gupta, Blake M. Warner, Osama Rahma, Jarushka Naidoo, Patrick A. Ott, David A. Hafler, Harriet Kluger, Arezou Khosroshahi, Rafeh Naqash, Lorinda Chung, Tamiko R. Katsumoto, Shivaani Kummar, Hussein Tawbi, Elad Sharon. A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT249.

e16677 Background: Nivo is FDA-approved in sorafenib-experienced, advanced HCC. Post-registration data to portray treatment in a real-world setting is lacking. Methods: We describe safety and efficacy of nivo in patients (pts) from 8 centres (USA n = 181, Asia n = 47, Europe n = 5), documenting overall (OS), progression-free survival (PFS), overall response (ORR) and disease control rates (DCR) (RECIST). Results: We analysed 233 pts, mostly cirrhotic (n = 176, 75%) due to hepatitis C (n = 95, 54.0%) with Barcelona Clinic Stage (BCLC) C HCC (n = 178, 76.4%), Child-Pugh class (CP) A (n = 158, 67.8%) or B (n = 75, 32.2%), and AFP > 400 IU/mL (n = 132, 56.7%). Nivo was given as first (1L, n = 85, 36.5%), second line (2L, n = 130, 55.8%) or > 2L (n = 18, 7.7%), after local (n = 191, 82%) and systemic therapy (n = 148, 63.5%), mostly sorafenib (n = 142, 60.9%). Median duration of nivo was 6.0 months (mo, interquartile range [IQR] 2.6-11.9) and stopped due to progression (n = 109, 46.8%) or toxicity (n = 8, 3.4%). After median follow up of 7 mo (IQR 3.0-12.3), ORR was 22.4% and DCR was 52.1%. Best responses (n = 219, 94%) included complete and partial responses in 18 (7.7%) and 31 (13.3%) pts respectively, stable disease in 65 (27.9%) and progressive disease in 105 (45.1%), not dissimilar by CP (p = 0.26). Median OS was 12.2 mo (95%CI 8.4-16.0) and predicted by CP (CPA 16.3 mo 95%CI 11.7-20.8; CPB 7.3 mo 95%CI 4.2-10.4; hazard ratio [HR] 1.9, p = 0.01), nivo line (1L 16.3 mo 95%CI 8.0-24.5; > 1L 10.4 mo 95%CI 7.4-13.5; HR 0.68, p = 0.05), and PVT (PVT- 13.8 mo 95%CI 11.7-16.0; PVT+ 10.4 mo 95%CI 7.8-13.0; HR 1.8, p = 0.015) but not cirrhosis, AFP, BCLC or steroid use (p > 0.05). Median PFS was 10.1 mo (95%CI 6.1-14.2), predicted by BCLC (A-B 19.0 mo 95%CI 7.1-30.8; C 8.2 mo 95%CI 4.9-11.4; HR 2.8, p = 0.002) and line (1L 18.2 mo 95%CI 10.4-25.9; > 1L 8.2 mo 95% CI 6.2-10.2; HR 0.60, p = 0.021), but not cirrhosis, AFP, or steroid use (p > 0.05). 26 pts (11.2%) suffered > = Grade 2 toxicities, most commonly fatigue (n = 29, 24.7%). Conclusions: Real-world use of nivo in advanced HCC across line of therapy suggests reproducible clinical efficacy and safety compared to prospective trials.

e16500 Background: Eosinophilic colitis (EoC) is a rare form of eosinophilic gastrointestinal disease characterized by diffuse eosinophilic infiltration in the deep lamina propria and extensive crypt epithelial injury with apoptosis and crypt abscesses. The pathophysiology is still unclear and associated with many etiologies. We described the clinical characteristics of EoC in cancer patients. Methods: We retrospectively reviewed the pathology report of the colonic samples from endoscopy or surgical resection obtained between 01/2000 and 12/2018 at MD Anderson Cancer Center. The included cases had significant eosinophilia with key word description of “numerous”, “many” or “dominant” on the pathology. Clinical data were collected and analyzed. Results: A total of 41 cases were included based on the inclusion criteria with 34% men, with a median age of 60. 27% had NSAID use and 40% were smokers. One-fourth had co-existing autoimmune conditions. 78% had cancer diagnosis (hematologic at 41%, followed by genitourinary and gastrointestinal origin) with the rest carrying no cancer diagnosis. Half of the cases received chemotherapy with median duration of 180 days between chemotherapy to EoC onset. Common EoC symptoms included diarrhea, and abdominal pain which were present in 76% patients. Diarrhea was more prevalent in patients who received chemotherapy (85% vs 42%). Median duration of EoC symptoms was shorter in cancer patients (240 vs 30 days) and chemotherapy exposure (120 vs 30 days). Hospitalization for EoC was required in 15% cases. Most commonly administered treatment for EoC was immunosuppressants (22%). Normal colonoscopy was reported in 88% patients at the time of EoC diagnosis. All-cause mortality was 37% and was mostly related to underlying malignancy. Conclusions: The disease course of EoC in cancer patients on chemotherapy is not well defined. It appeared to be less severe than non-cancer patients, which raised the possibility of two separate subclasses of this disease entity. Cancer/chemotherapy related EoC could be a GI specific paraneoplastic manifestation, and behave differently from other etiology. [Table: see text]

3067 Background: ICIs are efficacious treatment for several advanced malignancies. IMC can limit their use, and can be refractory to medical treatment (immunosuppression) with significant morbidity. Gut microbiome alteration affects IMC development. We sought FMT as a novel therapy for IMC refractory to immunosuppressive therapy. Methods: 15 patients who received FMT for IMC after failure of immunosuppressive therapy were included (6/2017-1/2020). FMT was performed via colonoscopy with healthy donor’s stool. Results: Median age was 55 years with 67% males. 5 patients received PD(L)-1, one CTLA-4 and 9 on combination. Majority had genitourinary cancers followed by melanoma. Median time from ICI to IMC was 75 days. 14 patients had grade 3-4 diarrhea and 9 had grade 3-4 colitis. Endoscopy showed mucosal inflammation in 12 patients and normal mucosa in 3 patients. IMC was refractory to 2-3 doses of infliximab or vedolizumab after corticosteroids prior to FMT. Median time from IMC onset to FMT was 75 days. 13 patients received one . 11 patients achieved clinical response within 10 days of FMT (7-14). Symptom remission was maintained for a median follow-up of 13 months. 6 patients resumed non ICI cancer treatments after FMT. 4 patients had persistent symptoms; 2 continued on vedolizumab, 1 had total colectomy, and 1 transferred to hospice. 4-8 weeks after FMT, endoscopic remission was achieved in 64% of the 11 patients who responded to FMT. No adverse events were reported. Conclusions: FMT treatment was successful in 73% of patients with for IMC refractory to immunosuppressive therapy. Controlled clinical trials are warranted to confirm our conclusion. [Table: see text]

TPS3158 Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for an increasing number of solid tumors and hematological malignancies. However, patients (pts) with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flares and worsening of pre-existing autoimmune disorders in pts with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to pts with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, Sjögren's Syndrome and Other Autoimmune Disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in pts with autoimmune diseases and advanced malignancies (NCT03816345). The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in pts with autoimmune disorders and advanced malignancies. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced malignancies in which ICI are approved or have shown clinical activity. Key overall exclusion criteria include prior therapy with anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 pts will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is enrolling pts through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345 .

e24048 Background: Cancer patients are at a significantly increased risk of rCDI by virtue of a compromised immune function from underlying malignancy, anti-cancer therapy and frequent antibiotic use for opportunistic infections. Furthermore, cancer patients have shown to have a lower response rate to standard oral antibiotics for CDI. Data is limited in regards to the safety and efficacy of FMT in managing rCDI in cancer patients. We aim to describe our experience of the same at a tertiary care cancer center. Methods: We conducted a retrospective study of cancer patients who underwent FMT for rCDI at the MD Anderson Cancer Center 06/2017-01/2020. FMT was performed through colonoscopy with universal donors’ stool. Baseline clinical data were collected and analyzed. Results: Our sample comprises 19 patients of whom 12 had solid tumors and 7 hematological malignancies, most of which were stage 4 at the time of FMT. The mean age was 66.5 years. Most patients received proton pump inhibitor, antibiotics and cancer therapy within 3-6 months of FMT. On average, each patient had 3 episodes of CDI, received 4 courses of antibiotic treatments, and required 4 CDI related hospitalizations within 1 year prior to FMT. Majority of the CDI episodes were managed with a combination of antibiotics. Bezlotoxumab was used in 4 cases. 18 patients received FMT once, while one patient was treated with FMT thrice. Clinical response was seen in 74% patients with a median time of 1 day. 5 patients had refractory CDI including 3 recurrent rCDI, and 2 persistent symptoms. Compared to patients with good response, these refractory cases received more frequent antibiotics following FMT (100% vs 43%, p=0.033). Side effects were mostly mild GI complaints in 15.8% patients with no serious adverse events or mortality related to FMT. Conclusions: Our study shows that FMT is a safe and effective treatment for rCDI in cancer patients and provides rapid resolution of symptoms; Subsequent antibiotic use for the management of cancer related complications can negatively affect the efficacy of FMT. [Table: see text]

TPS2088 Background: ICIs have become the therapeutic standard for many cancers but are associated with unique and diverse irAEs that often occur at home. Appropriately timed and specific interventions are critical to recovery. Thus, there is a need to effectively & efficiently monitor in real time pts treated with ICIs. To improve outcomes, we have activated a clinical trial developed to determine the feasibility and safety of an electronically enabled strategy to remotely monitor symptoms and prompt communication that will guide and inform specific patient-driven “course corrections” in response to potential irAEs. Methods: This is an adaptive prospective trial that uses a mobile irAE-specific PRO application we developed to monitor and alert the care team in real time when severe symptoms are reported. In parallel with the mobile symptom collection, serum and urine biomarkers are collected at baseline, first tumor restaging, and upon the development of irAEs. Optional stool microbiome analyses are also performed. To facilitate the generalizability of our inferences, we are using broad inclusion criteria: ECOG performance status ≤3; any line of ICI given as standard of care or as part of therapeutic clinical trials; elderly pts are included. Because the relationship between PROs and irAEs is currently undefined, we designed our trial to use adaptive symptom thresholds that will notify the healthcare team of suspicion for irAEs. The mobile application will use these dynamic thresholds to determine whether or not to alert the healthcare team. The positive and negative predictive value of each symptom for identifying subsequent irAEs will be assessed at scheduled interim analysis time points. The care teams’ responses to the alerts, and all of the clinical outcomes for the pts over time will be collected as part of the trial. The primary goal of the trial is the assessment of the predictive power of the mobile PRO symptom collection in combination with serum and urine markers to identify grade 2 or higher adverse events that require intervention (e.g., dose modifications, hospitalizations, and therapeutic interventions) within two weeks of symptom onset. Effective remote monitoring of irAEs will leverage our understanding of ICI toxicity and empower pts to be effective partners in their care. The trial has currently enrolled 17 pts towards the enrollment target of 100 pts. Clinical trial information: PA19-0095 .

e15102 Background: Immune checkpoint inhibitors (ICIs) are efficacious in treating many advanced malignancies. However, drug induced colitis limits their use significantly. We present cases with chronic refractory ICI colitis requiring long term immunosuppressive therapy and favorable cancer outcomes. Methods: We identified 3 cases who developed ICI colitis and persisted for longer than 6 months requiring long term immunosuppressant therapy. The patients’ clinical data was collected. Results: All patients were male, with median age of 55. Two had melanoma, one urothelial cancer. All patients received PD-1(L)-1 agents with colitis onset about 3-6 months after ICI treatment. All patients were taken off ICI permanently due to colitis over a duration of 19-30 months (peak grade of 3). Endoscopy of all three were grossly unremarkable, with lymphocytic colitis on pathology in all three. Patient A’s colitis achieved clinical and histological remission after 5 doses of vedolizumab, however recurred after 9 months with biopsy proven recurrence. Current management is anti-diarrheal medication given mild symptom. Patient B had more aggressive disease, with first recurrence after 2 doses of infliximab and steroid, achieved initial histological remission after 3 doses of vedolizumab and 2 additional infliximab, then had 2nd recurrence after 3 months. Fecal microbiota transplantation as compassionate treatment was not effective. Thereafter, patient was resumed on vedolizumab ever since with clinical remission. Last histology evaluation showed persistent lymphocytic colitis 30 months after initial diagnosis. The third case had initial histological remission after 3 doses of vedolizumab, followed by recurrence after 4 months, which triggered another 3 doses of vedolizumab, with persistent grade 3 diarrhea despite resolution of histological inflammation after total 6 doses of vedolizumab. Patient was subsequently treated with steroid and ustekinumab with clinical remission. At the end of follow up, all three patients have sustained cancer remission over 19-31 months. Conclusions: IMC is a common adverse event from ICI, and could progress to a chronic inflammatory condition that require long term treatment. Histological remission does not preclude future recurrence of colitis. Persistent toxicity could be a surrogate marker for enduring ICI effect which may be associated with favorable cancer outcome. Long term immunosuppression can be essential for refractory ICI colitis cases for clinical remission.

e15166 Background: ICI therapies have revolutionized the landscape of cancer treatment. However, their increased use has also contributed to adverse events, e.g. IMDC. Clinically it is difficult to distinguish between infectious etiology or IMDC. It is unclear whether antimicrobial treatment substantially impacts the disease course. Here, we evaluated the characteristics and outcome of IMDC in cancer patients with superimposed diarrheagenic GI infections. Methods: We retrospectively evaluated cancer patients who received ICI with clinical symptoms of IMDC and confirmed stool microbiology of E. coli or non-CMV viral infections either at the time of IMDC, or within 60 days after IMDC diagnosis at MD Anderson Cancer Center 01/2011-08/2019. We described the disease course and outcome of IMDC based on their status of GI infection and antimicrobial treatment. Results: Total 72 patients were included, among them, 50 control patients with IMDC and no GI infection, 22 had diarrheagenic infections, composed of 17 E coli pathogens: Enteropathogenic, Enterotoxigenic, Enteroaggregative, and E coli 0157:H7 serotype; and 5 viral etiologies: Adenovirus, Norovirus, and Sapovirus. Patients in the infection group had higher grade of colitis (42.9% vs 18.4%, P = 0.041), and more frequent hospitalization (86.4% vs 62%, P = 0.052). 68.2% patients in the infection group received infliximab/vedolizumab add-on treatment compared to 40% in the no infection group (P = 0.078). Patients with GI infection and antimicrobial treatment had much higher IMDC recurrence rate than no antimicrobial treatment (50% vs 0, P = 0.015). GI infection was not associated with higher IMDC recurrence or worse overall survival of these patients. Conclusions: IMDC can occasionally be complicated by infection from common GI pathogens. Antimicrobial treatment was mostly used in severe IMDC cases and did not circumvent the need for immunosuppressant or improve the clinical outcomes. GI infection was not associated with higher IMDC recurrence or worse overall survival of these patients. [Table: see text]

Different chemical substances make different contributions to particles with different diameters. It is important to determine which species play important roles to control air pollution. In this study, the concentrations of water-soluble inorganic ions, elemental carbon, organic carbon and metal elements in PM1 (particulate matter with a diameter less than 1 μm) and PM2.5 (particulate matter with a diameter less than 2.5 μm) in the Shijiazhuang suburban area were measured by synchronous sampling for one month in the summer of 2016. The results showed that the chemical components of particulate matter are mainly SO42−, NO3−, NH4+ and organic matter (OM), accounting for 14%, 8%, 11%, and 11%, respectively, in PM1 and 13%, 8%, 10%, and 9%, respectively, in PM2.5. PM1 and PM2.5 have similar sources, including secondary nitrate, secondary sulfate, industrial sources, motor vehicle sources, dust, biomass combustion and coal burning, which contribute 29%, 30%, 10%, 9%, 8%, 8% and 6%, respectively, to PM1 and 29%, 33%, 12%, 13%, 8%, 2%, and 4%, respectively, to PM2.5. Based on the analysis of a typical pollution episode, the concentrations of PM1 and PM2.5 increase synchronously in the explosive growth stage, with nitrate acting as the key chemical component. In the most polluted period, the concentration of PM2.5 continues to increase because of the increase in sulfate, while that of PM1 is almost constant. The results show that the prevention and control of PM1 and PM2.5 should be different in different pollution stages.

531 Background: The impact of corticosteroid treatment (CT) on the efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) is undefined. We evaluated whether CT administered at baseline (bCT) or concurrently to ICI (cCT) influences clinical outcomes of HCC patients treated with ICI. Methods: This retrospective, multi-center observational study was conducted across 9 tertiary academic referral centers collected 341 HCC patients who received ICI across 3 continents between January 1, 2016 and April 1, 2019. Outcome measures included overall (OS) and progression-free survival (PFS) calculated from time of ICI commencement and overall response rates (ORR) defined by Response Evaluation Criteria in Solid Tumors (v1.1) on 6-8 weekly periodic restaging. Results: Of 331 eligible patients, 254 (76%) had BCLC-C stage HCC and received mostly PD(L)-1 ICI monotherapy (n=250, 85%). Median OS was 12.1 months (95%CI 9.2-15.0 months) and median PFS was 8.1 months (95%CI 6.3-10 months). In total 81 patients (24%) received >10 mg prednisone equivalent daily either as bCT (n=15, 4%) or cCT (n=66, 20%). Indications for CT included procedure/prophylaxis (n=37, 45%), management of irAE (n=31, 37%), cancer-related symptoms (n=5, 2%) or comorbidities (n=8, 3%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in uni- and multi-variable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (2.4 vs. 11.3 months, p=0.01), OS (4.5 vs. 12.8 months, p=0.05) and reduced ORR (p=0.03) compared to cancer-unrelated indications. Conclusions: This is the first study to demonstrate that neither bCT nor cCT appear to influence response and OS following ICI in HCC. Worse survival and ORR in CT recipients for cancer-related indications appears driven by the poor prognosis associated with symptomatic HCC.

Immune checkpoint inhibitors (ICIs) have been increasingly used for multiple cancer types in the past decade. ICIs include CTLA-4 inhibitors (e.g., ipilimumab) and the PD-1 and PD-L1 inhibitors (e.g., nivolumab and pembrolizumab). Hepatotoxicity is not uncommon secondary to ICI treatment. It can occur 8-12 weeks after the initiation of ICI and presents with elevation of aspartate transaminase and alanine transaminase. ICI-induced hepatitis is usually asymptomatic but may present with fever, malaise, and even death in rare cases. It is a diagnosis of exclusion after other etiologies are excluded based on medical history, laboratory evaluation, and imaging and histological findings. ICI-induced hepatitis might require discontinuation of ICI and/or treatment with immunosuppressants.

Background Immune-mediated diarrhea and colitis (IMDC) can limit immune checkpoint inhibitors (ICIs) treatment, which is efficacious for advanced malignancies. Steroids and infliximab are commonly used to treat it. These agents induce systemic immunosuppression, with its associated morbidity. We assessed clinical outcomes of vedolizumab as an alternative treatment for IMDC. Methods We analyzed a retrospective case series of adults who had IMDC refractory to steroids and/or infliximab and received vedolizumab from 12/2016 through 04/2018. Results Twenty-eight patients were included. The median time from ICI therapy to IMDC onset was 10 weeks. Fifteen patients (54%) had grade 2 and 13 (46%) had grade 3 or 4 IMDC. Mucosal ulceration was present in 8 patients (29%), and nonulcerative inflammation was present in 13 (46%). All patients had features of active histologic inflammation; 14 (50%) had features of chronicity, and 10 (36%) had features of microscopic colitis concurrently. The mean duration of steroid therapy was 96 days (standard deviation 74 days). Nine patients received infliximab in addition to steroids and their IMDC was refractory to it. Among these, the duration of steroid use was 131 days compared with 85 days in patients who did not receive infliximab. Likewise, patients who failed infliximab before vedolizumab had a clinical success rate of 67% compared to 95% for patients that did not receive infliximab. The median number of vedolizumab infusions was 3 (interquartile range 1–4). The mean duration of follow-up was 15 months. Twenty-four patients (86%) achieved and sustained clinical remission. Repeat endoscopic evaluation was performed in 17 patients. Endoscopic remission was attained in 7 (54%) of the 13 patients who had abnormal endoscopic findings initially; 5/17 patients (29%) reached histologic remission as well. Conclusions Vedolizumab can be appropriate for the treatment of steroid-refractory IMDC, with favorable outcomes and a good safety profile. Electronic supplementary material The online version of this article (10.1186/s40425-018-0461-4) contains supplementary material, which is available to authorized users.

Background Cancer patients are susceptible to recurrent Clostridium difficile infection (CDI) that is increasing globally, necessitating new approaches to prevent fatal consequences. We examined the clinical characteristics of cancer patients with recurrent CDI (RCDI). Patients and methods A retrospective review of cancer patients with C. difficile-positive test between January 2015 and May 2017 was carried out. CDI was defined as diarrhea and toxigenic C. difficile detection in the stool by nucleic acid amplification test and enzyme immunoassay. Patients having two CDI episodes were categorized as single recurrent CDI (SRCDI), and those having three or more CDI episodes were categorized as multiple recurrent CDI (MRCDI). Treatment failure was defined as the requirement of antimicrobial alteration or repetition. Results We included 170 patients having 270 CDI episodes; 85 patients had non-RCDI, and 85 had RCDI; 14 of them had MRCDI. Previous hospitalization and immunosuppressant use were more frequent in MRCDI group than in SRCDI group (P=0.009 and 0.002, respectively). Physicians treated more SRCDI episodes than MRCDI episodes with metronidazole alone (P=0.017), whereas, more MRCDI episodes needed combination antimicrobials (P=0.072). The mean duration of CDI treatment was longer in the MRCDI group than in the SRCDI group (P=0.030). MRCDI was associated with treatment failure more than SRCDI (P=0.021). The risk for a recurrent episode of CDI was increased in patients who had the following features of the first CDI episode: previous use of antibiotic, NSAID, immunosuppressant, chemotherapy, comorbidities, CDI treatment failure, and severe CDI (P Conclusion Risk factors for RCDI in cancer patients are similar to those without cancer, with the exception of chemotherapy that is only given to cancer patients. Long CDI treatment and CDI treatment failure are associated with MRCDI.

Background Immune checkpoint inhibitors (ICPI) are efficacious treatments for advanced malignancies but can result in immune mediated diarrhea and colitis (IDC). Currently, the guidelines for the treatment of IDC depend only on clinical symptoms. Endoscopic and histologic features of such adverse events are not well studied in a manner that can help to gauge treatment plans. We aimed to characterize endoscopic and histologic features of IDC and to assess their association with clinical outcomes. Methods Our study included patients who had undergone endoscopy for IDC (1/2010 to 3/2018). Patients with GI infection at time of onset were excluded. High-risk endoscopic features were ulcers deeper than 2 mm, larger than 1 cm, and extensive colonic involvement. Univariate and multivariate logistic regression were performed to assess the association of endoscopic and histological features with clinical outcomes. Results A total of 182 patients was included; most were white (92%), males (65%) with a mean age of 60 years. Median time from ICPI initiation to IDC was 7 weeks. Fifty-three percent had grade 3–4 diarrhea, and 32% grade 3–4 colitis. Forty-nine patients had mucosal ulcerations, 66 non-ulcerative inflammation and 67 normal endoscopy. Calprotectin was higher in patients with ulceration (P = 0.04). The sensitivity of lactoferrin to detect histologic and endoscopic inflammation was 90% and 70% respectively. Patients who underwent endoscopy earlier than 7 days after IDC onset had shorter duration of IDC symptoms and duration of steroid treatment than those who underwent endoscopy after 7 days of IDC onset (P = 0.026 and P = 0.053, respectively). Patients who underwent endoscopy > 30 days of symptom onset required longer duration of steroids (P = 0.02), had more recurrent symptoms (P < 0.01) and received later infliximab/vedolizumab add-on therapy than did those who underwent endoscopy ≤30 days (P = 0.03). High-risk features were associated with more frequent (P = 0.03) and longer duration (P = 0.02) hospitalization and infliximab/vedolizumab requirement (P < 0.01). Patients with active histological inflammation had more recurrence (P < 0.01) and repeat endoscopy (P < 0.01). Repeat endoscopy was required in 47 patients. A multivariate logistic regression revealed that longer ICPI treatment was associated with more frequent hospitalizations (OR 1.00; 95%CI 1.00–1.01; P < 0.01) and high-risk endoscopic features were associated with the requirement of infliximab/vedolizumab (OR 3.89; 95%CI 1.68–9.01; P < 0.01). Conclusion High risk endoscopic features and active histologic inflammation represent important markers of disease severity with clinical implications and should be used in a timely manner to devise IDC-focused treatment algorithms.

Salvia miltiorrhiza Bunge is a traditional Chinese medicine, and its water-soluble phenolic acid active compounds have very important medicinal value; however, the synthesis pathways of the main active ingredients remain unknown. Here, we employed nuclear magnetic resonance (NMR)-based metabolomics and transcriptomics techniques to study the biosynthesis mechanism of salvianolic acids. High-performance liquid chromatography (HPLC) combined with NMR showed an improvement over traditional techniques, and 54 metabolites were detected. The results of the multivariate statistical analysis showed that salvianolic acid B (SAB), rosmarinic acid (RA), caffeic acid, succinate, and citrate were among the multiple compounds that were increased in the methyl jasmonate (MeJA)-elicited group; the levels of sucrose, fructose, glutamine, and tyrosine were decreased. Combined with the differentially expressed genes (DEGs) found by transcriptome sequencing, we speculate that the synthesis of RA after MeJA treatment mostly occurred through caffeic acid and bypassed 4-hydroxyphenyllactic acid. This provides useful information for the study of salvianolic acids synthesis.

Hyperlipidemia is one of the main causes of obesity, type 2 diabetes mellitus (T2DM), and atherosclerosis. The adenosine derivative, 2',3',5'-triacetyl-N

The compound 2',3',5'‑tri‑O‑acetyl‑N

Background Immune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients’ outcomes. Methods This retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups. Results Diarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (n = 44) or with infliximab (n = 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (P 30 days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, P = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, P = 0.089). Conclusions Patients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system–based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Background Diarrhea and colitis are the second most common immune checkpoint inhibitor (ICPI)-induced adverse events. However, a comprehensive characterization of the endoscopic and histologic features of ICPI-induced diarrhea and colitis is lacking. Therefore, we aimed to describe endoscopic and histologic features of ICPI-induced gastrointestinal toxicities and to assess their association with patients' clinical characteristics and outcomes. Methods We retrospectively reviewed records of 53 patients with ICPI-related diarrhea/colitis between 2011 and 2017. We collected data on demographics, diarrhea/colitis grade, treatment, and endoscopic and histologic findings. Long-term follow-up included repeat endoscopy findings, diarrhea recurrence, and overall survival. We compared groups by treatment, endoscopic and histologic findings, and constructed Kaplan-Meier survival curves. Results Most patients had grade 2 or higher diarrhea (87%) and colitis (60%). Thirty-one patients were successfully treated with corticosteroids, and 22 additionally required infliximab. On endoscopy, 21 (40%) patients had ulcerations and 22 (42%) had nonulcerative inflammation. Patients with ulcerations had more steroid-refractory disease (P = 0.044) and high-grade diarrhea (P = 0.033). Histology showed mostly acute (23%) or chronic (60%) inflammation. During mean follow-up duration of 18.9 months, 19 (36%) developed recurrent diarrhea. Most patients had persistent endoscopic (8/13, 62%) and histologic (9/11, 82%) inflammation. Patients with higher-grade adverse events had improved survival. Higher-grade colitis was associated with endoscopic inflammation (P = 0.039), but grade of diarrhea was not associated with endoscopic inflammation or grade of colitis. Conclusion 10.1093/ibd/izy104_video1izy104.video15808053084001.

Immune checkpoint inhibitors (ICIs) have been increasingly used for multiple cancer types in the past decade. ICIs include CTLA-4 inhibitors (e.g., ipilimumab) and the PD-1 and PD-L1 inhibitors (e.g., nivolumab and pembrolizumab). Hepatotoxicity is not uncommon secondary to ICI treatment. It can occur 8–12 weeks after the initiation of ICI and presents with elevation of aspartate transaminase and alanine transaminase. ICI-induced hepatitis is usually asymptomatic but may present with fever, malaise, and even death in rare cases. It is a diagnosis of exclusion after other etiologies are excluded based on medical history, laboratory evaluation, and imaging and histological findings. ICI-induced hepatitis might require discontinuation of ICI and/or treatment with immunosuppressants.

Figure S1. Incidence of colitis. Figure S2. Flow chart of endoscopic findings, histologic features, and immunosuppressive treatment. Figure S3. Endoscopy images demonstrating: (a) high-risk features, (b) low-risk features, (c) Ulcerative colitis like disease, (d) Crohn’s like disease; yellow arrow demonstrates large deep mucosal ulceration surrounded by normal mucosa. Figure S4. Histopathology images demonstrating: (a) colonic mucosa with architecture distortion, basal plasmacytosis (white arrow), cryptitis (yellow arrow) and crypt abscess (red arrow), (b) Colonic mucosa with mild architecture distortion and minimal evidence of active inflammation. Figure S5. Kaplan-Meier curve showing comparable overall survival between patients with active histological inflammation and those with no active inflammation (P = 0.1087). Figure S6. Kaplan-Meier curve showing comparable overall survival between patients with high-risk endoscopic features and those without (P = 0.7377). Figure S7. Kaplan-Meier curve showing comparable overall survival rates between patients who received immunosuppression for IDC and those who did not (P = 0.2914). Figure S8. Kaplan-Meier curve showing comparable overall survival between patients who had grade 1–2 and those who had grade 3–4 diarrhea (P = 0.7965). (DOCX 5087 kb)

Immune checkpoint inhibitors (ICIs) have shown significant benefit in cancer patients, but are associated with immune-related adverse events (irAEs), that can affect the gastrointestinal tract resulting in diarrhea and colitis. IrAEs range from mild self-limiting to severe life-threatening disease, which potentially limit the use of these medications. Diagnosis of ICI-induced colitis is based on clinical symptoms, physical examination, stool tests, endoscopic evaluation, and/or imaging. Current management strategy is mainly anti-diarrheal agents for mild symptoms, and immunosuppressants (e.g., corticosteroids, and infliximab or vedolizumab) for more severe cases.

Background Neoantigens derived from tumor-associated mutations can elicit T cell-mediated antitumor immunity and facilitate tumor rejection. Here, we assessed the safety and efficacy of personalized neoantigen peptide vaccination (PPV) in advanced NSCLC patients who had failed conventional therapy. Methods 24 stage III/IV recurrent NSCLC patients were immunized with mixtures of short and long neoantigen peptides based on personalized tumor-associated mutations and predicted HLA peptide binding affinities. Primary study endpoints were feasibility and safety. Secondary endpoints were PPV-induced immune responses, progression-free survival (PFS) and overall survival (OS). Results Aside from transient rash, fatigue and/or fever in 3 patients, no treatment-related adverse events were observed. The median PFS and OS of the 24 PPV patients was 6.0 and 8.9 months, respectively. Of the 16 PPV patients bearing EGFR mutations, 7 experienced objective tumor response by RECIST 1.1, including 6 PR and 1 CR. Of the 8 patients expressing wild-type EGFR, 4 showed SD and no PR or CR. Importantly, 9 PPV patients who continued EGFR inhibitor (EGFRi) therapy in spite of prior progression showed extended survival compared to 7 patients who stopped EGFRi prior to initiating PPV (median OS: 13.8 vs. 7.6 months, P = 0.038), though both patient groups experienced similar objective response rates. Immune monitoring demonstrated the immunogenicity of two highly shared EGFR mutations in multiple responding patients. Robust PPV-specific immune responses were observed in 4 responding patients, with ELISPOT and tetramer staining showing incremental increases in peripheral blood neoantigen-specific CD8+ T cell frequencies for up to 3 months during PPV. T-cell receptor (TCR) Vb sequencing also demonstrated significantly increased frequencies of neoantigen-specific CD8+ TCR clones in both peripheral blood and tumor-infiltrating lymphocytes following PPV. Conclusions These results suggest that PPV is safe and potentially beneficial for advanced stage EGFR-mutated NSCLC patients. Survival analyses imply that PPV in combination with EGFRi may be a viable treatment option for NSCLC, in spite of prior EGFRi failure. Clinical trial identification ChiCTR-INR-16009867. Legal entity responsible for the study Tianjin Beichen Hospital. Funding Tianjin HengJia Biotechnology Development Co., Ltd. Disclosure F. Li: Shareholder / Stockholder / Stock options: Tianjin HengJia Biotechnology Development Co., Ltd. G. Lizee: Advisory / Consultancy: HengJia Neoantigen Biotechnology (Tianjin) Co., Ltd. P. Hwu: Advisory / Consultancy: Dragonfly Therapeutics; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Immatics; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Genentech. L. Deng: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. Q. Zou: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. M.A. Stairs: Advisory / Consultancy: HengJia Neoantigen Biotechnology (Tianjin) Co., Ltd. C. Chen: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. C. Huo: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. Y. Wang: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. All other authors have declared no conflicts of interest.

In recent years, research of acid sensing ion channels (ASICs) has increased tremendously, especially studies focusing on ASIC1a, which plays a critical role in many important physiologic and pathological functions. This review will discuss factors regulating ASIC1a expression and activity in various conditions and will provide a theoretical basis for clinical development and application of ASIC1a modifiers.

The alpine wetlands on the Tibetan Plateau (TP) constitute 30% of China's wetlands, and previous studies have considered these wetlands to be important sources of CH4, based on several swamp measurements from the eastern edges of the plateau. However, the alpine wetlands consist of both swamps (9.5%) and swamp meadows (79.8%). In this study, the CH4 fluxes of a swamp meadow and a swamp were determined. The results showed that the swamp meadow emitted much less CH4 (130.8 ± 123.9 µg m−2 h−1) than the swamp (2795.2 ± 796.4 µg m−2 h−1). The CH4 fluxes within the swamp meadow showed distinct microscale spatial heterogeneity: the hollow terrain released CH4, while the hummocks absorbed CH4; this pattern was explained well by soil moisture. The CH4 emissions in the swamp meadow were highly sensitive to soil temperature variation (Q10 = 3.62), while they were more sensitive to soil moisture in the swamp. By summarizing existing measurements, and considering the differences in CH4 emissions from swamp meadows and swamps, the emissions of CH4 from alpine wetlands across the TP were recalculated to range from 0.215 to 0.412 Tg CH4 a−1, lower than previous studies. By comparison, the CH4 uptake by nonwetland ecosystems ranges from −0.68 to −0.53 Tg CH4 a−1. Therefore, this study conveys a notion that the alpine wetlands on the TP may not be significant CH4 sources. However, further studies are needed to reduce the uncertainty regarding CH4 emissions.

Based on a network of field stations belonging to the Chinese Academy of Sciences (CAS), the Campaign on Atmospheric Aerosol Research network of China (CARE-China) was recently established as the country’s first monitoring network for the study of the spatiotemporal distribution of aerosol physical characteristics, chemical components, and optical properties, as well as aerosol gaseous precursors. The network comprises 36 stations in total and adopts a unified approach in terms of the instrumentation, experimental standards, and data specifications. This ongoing project is intended to provide an integrated research platform to monitor online PM2.5 concentrations, nine-size aerosol concentrations and chemical component distributions, nine-size secondary organic aerosol (SOA) component distributions, gaseous precursor concentrations (including SO2, NOx, CO, O3, and VOCs), and aerosol optical properties. The data will be used to identify the sources of regional aerosols, the relative contributions from nature and anthropogenic emissions, the formation of secondary aerosols, and the effects of aerosol component distributions on aerosol optical properties. The results will reduce the levels of uncertainty involved in the quantitative assessment of aerosol effects on regional climate and environmental changes and ultimately provide insight into how to mitigate anthropogenic aerosol emissions in China. The present paper provides a detailed description of the instrumentation, methodologies, and experimental procedures used across the network, as well as a case study of observations taken from one station and the distribution of main components of aerosol over China during 2012.

A regional chemical transport model, RAMS-CMAQ, was employed to assess the impacts of biosphere-atmosphere C2 exchange on seasonal variations in atmospheric C2 concentrations over East Asia. Simulated C2 concentrations were compared with observations at 12 surface stations and the comparison showed they were generally in good agreement. Both observations and simulations suggested that surface C2 over East Asia features a summertime trough due to biospheric absorption, while in some urban areas surface C2 has a distinct summer peak, which could be attributed to the strong impact from anthropogenic emissions. Analysis of the model results indicated that biospheric fluxes and fossil-fuel emissions are comparably important in shaping spatial distributions of C2 near the surface over East Asia. Biospheric flux plays an important role in the prevailing spatial pattern of C2 enhancement and reduction on the synoptic scale due to the strong seasonality of biospheric C2 flux. The elevation of C2 levels by the biosphere during winter was found to be larger than 5 ppm in North China and Southeast China, and during summertime a significant depletion (⩾ 7 ppm) occurred in most areas, except for the Indo-China Peninsula where positive bioflux values were found.

A quantitative nuclear magnetic resonance (qNMR) method to measure the content of Orlistat in tablets was studied and found to be efficient, accurate, reliable, and simple. In this paper, phloroglucinolanhydrous and dimethylsulfoxide-d6 (DMSO-d6) served as the internal standard and solvent, respectively. The qNMR methodology, including the linearity, range, the limit of detection (LOD) and quantification (LOQ), stability, precision, and accuracy, was validated seriatim, and the results were very favorable. The content determination results of three batches of Orlistat in tablets were almost identical upon comparing the qNMR method and the high-performance liquid chromatography (HPLC) method. The recommended method authentically compensated the deficiencies of the current HPLC method for determining Orlistat content, and proved to be a method complementary to traditional analysis for the purity measurement of Orlistat in some pharmaceutical preparations.

First- and second-generation Percec-type dendronized ferrocenyl norbornene macromonomers containing, respectively, three and nine ferrocenyl termini are synthesized and polymerized by ring-opening metathesis polymerization using Grubbs' third-generation olefin metathesis catalyst with several monomer/catalyst feed ratios between 10 and 50. The rate of polymerization is highly dependent on the generation of the dendronized macromonomers, but all these ring-opening metathesis polymerization reactions are controlled, and near-quantitative monomer conversions are achieved. The numbers of ferrocenyl groups obtained are in agreement with the theoretical ones according to the cyclic voltammetry studies as determined using the Bard–Anson method.

article The alpine steppe covers 700,000 km 2 on the central and western Tibetan Plateau, constituting a large portion of China's total grassland ecosystem. Yet, limited effort has been made to quantify its greenhouse gas fluxes and exam- ine how they will respond to increased reactive N deposition. Therefore, we conducted an experiment to simulate an elevated level of N deposition (10 kg N ha −1 a −1 ) to investigate the variability in GHG fluxes and their responses to the N treatment. h −1 ), but neither soil moisture nor temperature explained its variation. (2) Simulated N deposition significantly enhanced the plant community in the alpine steppe in terms of leaf tissue N content. However, nei- ther the seasonal pattern nor the CO2 efflux and CH4 uptake were significantly affected by the N additions, and the emission factors (EFs) of N2O varied from 0.16 to 0.85% (0.56 ± 0.20%).

The uptake of CH4 by aerate soil plays a secondary role in the removal of tropospheric CH4 , but it is still highly uncertain in terms of its magnitude, spatial, and temporal variation. In an attempt to quantify the sink of the vast alpine grasslands (1,400,000 km(2)) of the Tibetan Plateau, we conducted in situ measurements in an alpine steppe (4730 m) and alpine meadow (4900 m) using the static chamber and gas chromatograph method. For the alpine steppe, measurements (2008-2013) suggested that there is large interannual variability in CH4 uptake, ranging from -48.8 to -95.8 μg CH4 m(-2) h(-1) (averaged of -71.5 ± 2.5 μg CH4 m(-2) h(-1)), due to the variability in precipitation seasonality. The seasonal pattern of CH4 uptakes in the form of stronger uptake in the early growing season and weaker uptake in the rainy season closely matched the precipitation seasonality and subsequent soil moisture variation. The relationships between alpine steppe CH4 uptake and soil moisture/temperature are best depicted by a quadratic function and an exponential function (Q10 = 1.67) respectively. Our measurements also showed that the alpine meadow soil (average of -59.2 ± 3.7 μg CH4 m(-2) h(-1)) uptake less CH4 than the alpine steppe and produces a similar seasonal pattern, which is negatively regulated by soil moisture. Our measurements quantified--at values far higher than those estimated by process-based models--that both the alpine steppe and alpine meadow are considerable CH4 sinks, despite the cold weather of this high-altitude area. The consecutive measurements gathered in this study also highlight that precipitation seasonality tends to drive the interannual variation in CH4 uptake, indicating that future study should be done to better characterize how CH4 cycling might feedback to the more extreme climate.

Long-standing inflammatory bowel disease is associated with increased risk of developing colorectal adenocarcinoma. Significant intra- and inter-observers' variability exists in histologic interpretation of dysplasia in surveillance biopsies. In this study, we evaluated the utility of a panel of immunohistochemical markers in diagnosing inflammatory bowel disease-associated neoplasia. We reviewed 39 colectomy specimens with inflammatory bowel disease-associated neoplasia. In these 39 cases, we identified 172 foci of interest (5 normal, 58 negative for dysplasia, 15 indefinite for dysplasia, 59 low-grade dysplasia, 18 high-grade dysplasia, and 17 invasive adenocarcinoma). They were subjected to immunohistochemistry for TP53 and CK7. Logistic regression was used to evaluate their association with the presence of dysplasia. Receiver operating characteristic curves were used to determine the optimal cutoffs and assess the diagnostic performance of TP53 and CK7. Both TP53 nuclear staining and CK7 immunoreactivity gradually increased in the progression of inflammatory bowel disease-associated neoplasia (P0.0001). CK7 immunoreactivity increased along with the increase of inflammation severity (P=0.0002) as well as reactive changes (P=0.04) in the colonic mucosa. But TP53 nuclear staining was independent of either feature. When both TP538% and CK730% as identified from logistic regression and receiver operating characteristic curves were used to diagnose dysplasia, the specificity achieved as high as 95%. When either TP538% or CK730% was used to diagnose dysplasia, the sensitivity achieved was 82%. Our results suggested that a combination of CK7 and TP53 immunohistochemistry may be helpful in diagnosing inflammatory bowel disease-associated dysplasia in difficult cases.