Inhibition of CDK9 exhibits anticancer activity in hepatocellular carcinoma cells via targeting ribonucleotide reductase.

Cyclin-dependent kinase 9 (CDK9) inhibitors are a novel category of anticancer treatment for cancers. However, their effects on hepatocellular carcinoma (HCC) are rarely investigated. Human ribonucleotide reductase (RR, which consists of RRM1 and RRM2 subunits) catalyzes the conversion of ribonucleoside diphosphate into 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools, which play essential roles in DNA synthesis and DNA repair. In this study, we identified that CDK9 protein expression in adjacent non-tumor tissues predicted HCC patients' overall and progression-free survivals. The anticancer activity of a CDK9-selective inhibitor, LDC000067, on HCC cells was positively associated with its ability to inhibit the expression of RRM1 and RRM2. LDC000067 downregulated RRM1 and RRM2 expression through post-transcriptional pathway. Specifically, LDC000067 triggered RRM2 protein degradation via multiple pathways, including proteasome-, lysosome-, and calcium-dependent pathways. Furthermore, CDK9 positively correlates with RRM1 or RRM2 expression in HCC patients, and the expressions of these three genes were associated with the higher infiltration of immune cells in HCC. Taken together, this study identified the prognostic relevance of CDK9 in HCC and the molecular mechanism for the anticancer effect of CDK9 inhibitors on HCC.

Anlotinib dramatically improved pulmonary hypertension and hypoxia caused by Pulmonary Tumor Thrombotic Microangiopathy (PTTM) associated with gastric carcinoma: a case report.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare malignancy-related respiratory complication, demonstrating rapid progression of pulmonary hypertension (PH) and respiratory failure. Although a number of treatments have been attempted for patients diagnosed with or suspected of having PTTM, successful-treated cases of PTTM were mainly from imatinib therapy, which was a PDGF receptor inhibitor. Anlotinib was a novel tyrosine kinase inhibitor that targets VEGFR, FGFR, PDGFR, and c-kit. CASE PRESENTATION: We reported a patient of PTTM associated with gastric carcinoma, whom were treated with anlotinib, thereby exhibiting significant improvement of PH and respiratory dysfunction. CONCLUSION: Our case provides a new understanding of therapy to PTTM, with implications for defining anlotinib as candidate drug for PTTM. Clinical diagnosis and prompt initiation of anlotinib might be one of the strategies in patients with unstable PTTM.

Adenovirus diseases: a systematic review and meta-analysis of 228 case reports.

OBJECTIVE: The clinical characteristics of various adenovirus (ADV) infection are underexplored up till now. To investigate the risk factors, manifestation, current status of ADV species, treatment and prognosis of this disease. METHODS: We performed a Pubmed and Embase systematic review for case report reporting the ADV infection to analyze the clinical characteristics of disease. RESULTS: Initial database searched identified articles of which 168 (228 cases) were included in the final analysis. Previous solid organ transplantation [odds ratio (OR) = 3.45, 95% CI 1.31-9.08, P = 0.01], hematopoietic stem cell transplant (OR = 4.24, 95% CI 1.33-13.51, P = 0.01) and hematological malignancy (OR = 4.78, 95% CI 1.70-13.46, P = 0.01) were associated with increased risk of disseminated ADV infection. Use of corticosteroids (OR = 3.86, 95% CI 1.21-12.24, P = 0.02) was a significant risk factor for acquiring urinary tract infections. A total of six species (21 types) of ADV infection have been identified in 100/228 (43.9%) cases. ADV B was the most common species. ADV B species (26/60, 52.0% or 5/41, 12.2% P = 0.001) were more isolated in patients with ADV pneumonia. ADV C (13/15, 86.7% versus 35/86, 40.7% P = 0.001) species were more identified in patients with disseminated disease. The species associated with keratoconjunctivitis is only ADV D in our analysis. Urinary tract ADV infections were observed in ADV A/B/D species. Cidofovir (CDV) (82/228, 36.0%) remained the most commonly antiviral therapy in our cases, followed by ribavirin (15/228, 6.6%), ganciclovir (18/228, 7.9%), and brincidofovir (12/228, 5.3%). Brincidofovir was administered as salvage therapy in 10 cases. Death was reported in 81/228 (35.5%) patients. Mortality rate was higher among patients with gastrointestinal (GI) ADV infection (5/10, 50.0%), ADV pneumonia (20/45, 44.4%) and disseminated ADV infection (53/122, 43.4%). CONCLUSION: Previous solid organ transplantation, hematopoietic stem cell transplant and hematological malignancy were risk factors for disseminated ADV infection. Use of corticosteroids was significant for urinary tract ADV infection. Different species correlated with different clinical manifestations of infection. Mortality rate was higher among patients with GI disease, pneumonia and disseminated disease. Our review clarified the current treatment of ADV infections, and more treatment required further investigation.

Safety and use of pulmonary function tests: a retrospective study from a single center over seven years' clinical practice.

BACKGROUND: To promote the utilization of pulmonary function tests (PFT) through analyzing the data of PFT during the past seven years in one large teaching hospital in China. METHODS: Through a retrospective analysis, the allocation of full-time staff in PFT room, the demographic characteristics of patients, cost-effectiveness of PFT, positive rate and failure rate of PFT, adverse events were analyzed. RESULTS: 1) From 2012 to 2018, the numbers of PFT showed the trend of escalation year by year. The proportion of patients receiving PFT rose from 29.0/10,000 in 2012 to 34.7/10,000 in 2018. The best allocation of PFT room was 20-25/ person / day. 2) The number of PFT provided by Department of Pulmonary and Critical Care Medicine (PCCM) accounted for 97.2, 97.1, 97.3, 97.8, 97.8, 98.0, and 98.2% of the total cases of outpatient PFT in the same year. The top three departments in the inpatient department were Department of Thoracic Surgery, Department of General Surgery, and Department of Urinary Surgery, the total cases of PFT in these three departments accounted for 65.1, 64.4, 62.1, 63.5, 62.4, 65.3 and 69.1% of the total cases of inpatient PFT in the same year. 3) Data from 2018 showed that the revenue from PFT was about 3.7 million Chinese Yuan, and that the salary of personnel and expenditure on machine maintenance and wear were about 800,000 Chinese Yuan. 4) 58.2% of the patients who had undergone PFT had ventilatory dysfunction. 5) The average failure rate of PFT in the past seven years was 1.91%. 6) The main adverse events of PFT examination were dizziness, amaurosis, limb numbness, lip numbness and falls. The incidence rates were 0.49, 0.42, 0.41, 0.39, 0.44, 0.48, and 0.45% respectively, with an average of 0.44%. CONCLUSIONS: The number of PFT showed an upward trend in the past seven years, and the optimal staffing of PFT room was 20-25 cases per person per day. The positive rate of pulmonary dysfunction was 58.2%. The failure rate of PFT and the incidence of adverse events were very low, suggesting it is a simple and safe clinical examination. It's worthy of further popularization and promotion.

Autophagy and its role in pulmonary hypertension.

Pulmonary hypertension (PH) is a very common kind of pulmonary vascular disease, which can cause a heavier burden on patient's quality of life, even lead to death. Yet, the mechanism of PH is incomprehensive and not so clear nowadays. In recent years, more and more studies show that autophagy plays a pivotal role in the development of PH. Some modalities target on the formation or maturation of autophagosome that has emerged from our increasing knowledge of autophagy machinery, which may prevent or eliminate the process of PH. The deciphering of molecular selectivity of autophagy has also been a source of novel modulators that act specifically on selective forms of autophagy. Tremendous recent progress has opened a new possibility for modulating autophagy in complex diseases. Thus, autophagy may become a prospective choice for treatment of PH. Herein, we reviewed the literatures and discussed the role of autophagy in the development and treatment of PH.

Rap2b promotes proliferation, migration, and invasion of lung cancer cells.

Rap2b, a member of the guanosine triphosphate-binding proteins, is widely up-regulated in many types of tumors. However, the functional role of Rap2b in tumorigenesis of lung cancer remains to be fully elucidated. In this study, we investigated the effect of Rap2b on the lung cancer malignant phenotype, such as cell proliferation and metastasis. We found that Rap2b could promote the abilities of lung cancer cell wound healing, migration, and invasion via increasing matrix metalloproteinase-2 enzyme activity. Furthermore, Rap2b overexpression could increase the phosphorylation level of extracellular signal-regulated protein kinases 1/2. In conclusion, our results suggested that Rap2b may be a potential therapeutic target for lung cancer.

Primary tracheal papilloma disguised as asthma: A case report.

INTRODUCTION: Tracheal papilloma presenting as asthma is a rare occurrence. CASE STUDY: We report a case of a 32-year-old male patient who presented with features of asthma. Flexible bronchoscopy demonstrated a large growth arising from the lower end of the trachea. Successful treatment using snare loop and argon plasma coagulation (APC) of the polyploidal growth was performed via flexible bronchoscope. RESULTS: The patient had immediate relief of airway obstruction and histopathological examination of the neoplasm demonstrated features of papilloma. CONCLUSION: Primary tracheal papilloma is mimicker of asthma, CT scan should be considered in patients with persistent chronic cough, or stridor. Endoscopic papillectomy is a safe and effective treatment and should be considered as first-line therapy for tracheal papilloma.

Identification of boron-deficiency-responsive microRNAs in Citrus sinensis roots by Illumina sequencing.

BACKGROUND: Boron (B)-deficiency is a widespread problem in many crops, including Citrus. MicroRNAs (miRNAs) play important roles in nutrient deficiencies. However, little is known on B-deficiency-responsive miRNAs in plants. In this study, we first identified miRNAs and their expression pattern in B-deficient Citrus sinensis roots by Illumina sequencing in order to identify miRNAs that might be involved in the tolerance of plants to B-deficiency. RESULTS: We isolated 52 (40 known and 12 novel) up-regulated and 82 (72 known and 10 novel) down-regulated miRNAs from B-deficient roots, demonstrating remarkable metabolic flexibility of roots, which might contribute to the tolerance of plants to B-deficiency. A model for the possible roles of miRNAs in the tolerance of roots to B-deficiency was proposed. miRNAs might regulate the adaptations of roots to B-deficiency through following several aspects: (a) inactivating reactive oxygen species (ROS) signaling and scavenging through up-regulating miR474 and down-regulating miR782 and miR843; (b) increasing lateral root number by lowering miR5023 expression and maintaining a certain phenotype favorable for B-deficiency-tolerance by increasing miR394 expression; (c) enhancing cell transport by decreasing the transcripts of miR830, miR5266 and miR3465; (d) improving osmoprotection (miR474) and regulating other metabolic reactions (miR5023 and miR821). Other miRNAs such as miR472 and miR2118 in roots increased in response to B-deficiency, thus decreasing the expression of their target genes, which are involved in disease resistance, and hence, the disease resistance of roots. CONCLUSIONS: Our work demonstrates the possible roles of miRNAs and related mechanisms in the response of plant roots to B-deficiency.

Effects of Comorbid Depressive Symptoms and Diabetes Mellitus on Functional Dyspepsia in Older Patients.

Objective: Diabetes mellitus (DM) is a global epidemic; comorbid depressive symptoms are highly prevalent worldwide and commonly manifests as physical symptoms, including functional dyspepsia (FD), a gastrointestinal psychosomatic disorder. This study aimed to explore the effects of comorbid depressive symptoms and DM on FD in older patients. Methods: In total, 420 older patients with DM completed measures of depression, anxiety, and FD. Relevant demographic characteristics and medical information were self-reported and obtained from the hospital information system. Results: Among older patients with DM, 30.48% had depressive symptoms. Patients with depressive symptoms were more likely to have FD than those without (42.19% vs. 20.21%, P = .000). Dyspepsia symptoms were more frequent in patients with depression (P = .022). The greater the amount of dyspepsia symptoms, the higher the depression symptoms score (P = .000). Furthermore, dyspepsia symptoms were positively correlated with depressive symptoms (r values were 0.292, 0.311, 0.297, 0.369; all had P < .05). Both FD subtypes, postprandial distress, and epigastric pain syndromes affected depressive symptoms (P < .05). Smoking was significantly associated with FD (P < .05). Diabetes mellitus complications, such as diabetic neuropathy, different therapeutic methods, and anxiety symptoms, influenced FD overlap (x 2 values were 6.298, 16.314, and 30.744; P < .05). Anxiety (odds ratio = 1.832, 95% Confidence Intervals (CI) 1.185-2.834) was a risk factor for FD in comorbid depressive symptoms and diabetes (P < .05). Conclusion: Comorbid depressive symptoms and DM overlapped with physical symptoms, such as FD, in older patients with DM. Lifestyle, diabetic factors, and anxiety were the associated risk factors.

[Expression of PD-1/PD-L1 in peripheral blood mononuclear cells in lung cancer patients and its biological significance].

OBJECTIVE: To analyze the expression of co-stimulatory molecules PD-1/PD-L1 in peripheral blood mononuclear cells in lung cancer patients, and to explore its biological significance. METHODS: One hundred and thirty-three lung cancer patients, 25 lung infection patients and 23 healthy donors were enrolled in this study. 100 µl of whole blood from these subjects were collected. Multi-color immunofluorescence staining and flow cytometry were used to detect PD-1/PD-L1 expression. The results were statistically analyzed. RESULTS: The expression level of CD3⁺CD8⁺ T cells in the lung cancer patients was (38.83 ± 1.74)%, significantly lower than that in the control group [(43.25 ± 3.35)%, P < 0.05]. CD8⁺CD28⁺ T cell subset in the peripheral blood of lung cancer patients was (17.73 ± 1.21)% significantly lower than that of the healthy donors [(27.96 ± 2.72)%, P < 0.01]. The CD8⁺CD28⁻ T cell subset was (21.19 ± 1.92)% in the lung cancer patients, significantly higher than that of the healthy control group [(15.18 ± 2.93)%, P < 0.05]. The expression level of PD-1 on the surface of CD8⁺CD28⁺ T cells was (10.67 ± 1.12)% in the group of lung cancer patients, significantly higher than that of the control group [(5.32 ± 1.58)%, P < 0.01]. It was also found that the expression of PD-1 on CD8⁺CD28⁻ T cells was up-regulated in the group of lung cancer patients (7.46 ± 1.25)%, significantly higher than that of the healthy control group [(2.68+1.07)%, P < 0.01]. The expression level of PD-L1 on CD68⁺ cells in the lung cancer patients was (16.03 ± 2.06)%, significantly higher than that of the healthy control group [(9.32 ± 2.00)%, P < 0.05]. CONCLUSION: Up-regulation of PD-1/PD-L1 on peripheral blood cells in lung cancer patients negatively regulates the lymphocytes, inhibits the immune response for killing tumor cells, and promotes tumor development and immune escape.

PF-429242 exhibits anticancer activity in hepatocellular carcinoma cells via FOXO1-dependent autophagic cell death and IGFBP1-dependent anti-survival signaling.

Effective therapies for hepatocellular carcinoma (HCC) are urgently needed, as it is a type of cancer resistant to chemotherapy. Recent evidence showed that PF-429242, a membrane-bound transcription factor site-1 protease (MBTPS1) inhibitor, exhibited anticancer activities against glioblastomas, renal cell carcinoma, and pancreatic cancer. However, its anticancer activity against HCC has yet to be investigated. In this study, we found that PF-429242 induced autophagy-dependent cell death in HCC cells. RNA-sequencing analysis indicated that the primary effect of PF-429242 was inhibition of the sterol regulatory element-binding protein (SREBP) signaling pathway. However, overexpression of SREBP proteins did not efficiently rescue PF-429242-induced autophagy and cell death. Mechanistically, PF-429242 induced forkhead box protein O1 (FOXO1)-dependent autophagic cell death. Additionally, PF-429242 caused FOXO1-independent upregulation of insulin-like growth factor-binding protein 1 (IGFBP1), ultimately leading to autophagy-independent cell death. The in vivo anticancer activity of PF-429242 against HCC cells was demonstrated in a tumor xenograft mouse model. Therefore, PF-429242 is a potential anticancer agent to treat HCC by triggering FOXO1-dependent autophagic cell death and IGFBP1-mediated anti-survival signaling in parallel.

Real-world tobacco cessation practice in China: findings from the prospective, nationwide multicenter China National Tobacco Cessation Cohort Study (CNTCCS).

Background: Tobacco cessation is proven to be the most effective and cost-effective strategy for smokers to reduce their risk of smoking-related disease and premature death. Providing effective, efficient, safe, and patient-centred tobacco cessation treatment to reach those who need them is a significant challenge. To date, only a few nationwide studies in China have assessed the overall clinical care practice and treatment outcome of tobacco cessation. Methods: This a prospective, nationwide, multicenter, cohort study covering all Eastern China, Northwest China, Central China, North China, Southwest China, Northeast China, and South China. Participants who were current smokers aged 18-85 years attending clinic for smoking cessation were included. All the participants were treated with 3-month cessation treatment and followed up for 3 months. Data were collected prospectively using online system. The primary outcome was 7-day point abstinence rate at 24 weeks, validated biochemically by an expired carbon monoxide level of less than 10 ppm. The participants lost to follow-up or not providing validation were included as non-abstainers. Findings: A representative sample of 3557 participants were recruited and 2943 participants were included into this analysis. These participants had mean age of 53.05 years, and 94.8% were males, with 75.8% showing symptoms of tobacco dependence. A total of 965 (32.8%) participants were treated with Bupropion + behavioural counselling, followed by 935 (31.8%) with behavioural counselling, 778 (26.4%) with Varenicline + behavioural counselling, 135 (4.6%) with alternative treatments + behavioural counselling, and 130 (4.4%) with nicotine replacement therapy (NRT) + behavioural counselling. After 3-month treatment and 3-month follow-up, 21.74% of the participants quit smoking at 24 weeks. In the multivariable-adjusted analyses, quitting smoking was significantly associated with female, higher socioeconomic status, poor health condition, different treatment received, and less smoking intensity. The tobacco cessation treatment varied widely across different areas of China. In particular, the areas with higher usage of cessation medication were associated with better cessation treatment outcome. Interpretation: The CNTCCS is the first large-scale nationwide cohort study of smoking cessation in China. Rich data collected from this prospective cohort study provided the opportunity to evaluate the clinical practice of tobacco cessation treatment in China. Funding: Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS 2021-I2M-1-010), Heilongjiang Provincial Science and Technology Key Program (2022ZXJ03C02), and National Key R&D Program of China (grant no. 2017YFC1309400).

[Clear cell tumor of the lung: report of seven cases and literature review].

OBJECTIVE: To study the clinical characteristics, chest imaging, pathology, diagnosis and treatment of clear cell tumor of the lung (CCTL). METHODS: Seven cases of CCTL diagnosed from January 2000 to December 2010 in our hospital, and 38 cases from literatures published in mainland of China, were retrospectively analyzed. RESULTS: The age of the patients was (44 ± 18) years, with equal sex distribution. In most of the patients, the lesions were incidentally found during routine examinations. Chest roentgenogram or CT scan showed a homogenous, rounded opacity (solitary nodule) of (3.2 ± 1.4) cm in diameter. Contrast-enhanced CT scans revealed a sign of intense enhancement because of these tumors were highly vascular, containing capillaries and sinusoidal vessels in some patients. Pathologic examination showed rounded and oval tumor cells with abundant clear cytoplasm, distinct cell borders, and cytoplasm rich in periodic acid Schiff-positive glycogen granules. Immunohistochemically, CCTL expressed melanocytic and myogenic markers, such as human melanoma black-45 (HMB-45), HMSA-1 and actin. But its epithelial markers were negative. Resection via operation was the only effective method till now. CONCLUSIONS: CCTL is a rare benign tumor with special features of clinical characteristics, radiology and pathology. The diagnosis is based on distinct pathologic characteristics. Earlier operation with long term follow-up is recommended.

Design and semisynthesis of oleanolic acid derivatives as VEGF inhibitors: Inhibition of VEGF-induced proliferation, angiogenesis, and VEGFR2 activation in HUVECs.

Angiogenesis inhibitors targeting the VEGF signaling pathway are developed into drugs for the treatment of vaious diseases, such as cancer, rheumatoid arthritis, and age-related macular degeneration. Recent studies have revealed that oleanolic acid (OA), a natural pentacyclic triterpenoid, inhibited the VEGF/VEGFR2 signaling pathway and angiogenesis in HUVECs, which may represent an attractive VEGF inhibitor. In this paper, rational structural modification towards OA was performed in order to improve its inhibitory effects aganist VEGF and anti-angiogenesis potential. As a result, a series of novel OA derivatives, possessing α,ß-unsaturated ketone system in ring A and amide functional group at C-28, were prepared and evaluated for cytotoxicity and their ability to inhibit VEGF-induced abnormal proliferation of HUVECs. The results showed that two promising derivatives, OA-1 and OA-16, exhibited no in vitro cytotoxicity against HUVECs but showed more potent inhibitory activity against VEGF-induced proliferation and angiogenesis in HUVECs, compared with OA. The results of Western blot indicated that OA-1 and OA-16 inhibited VEGF-induced VEGFR2 activation. Furthermore, small interfering RNA experiments were performed to confirm that both compounds inhibited VEGF-induced angiogenesis via VEGFR2. Thus, the present study resulted in the discovery of new promising OA-inspired VEGF inhibitors, which can serve as potential lead compounds for the treatment of angiogenesis-related diseases.

Ultralow-Power RRAM with a High Switching Ratio Based on the Large van der Waals Interstice Radius of TMDs.

Low power and high switching ratio are the development direction of the next generation of resistive random access memory (RRAM). Previous techniques could not increase the switching ratio while reducing the SET power. Here, we report a method to fabricate low-power and high-switching-ratio RRAM by adjusting the interstice radius (rg) between the van der Waals (vdW) layers of transitional-metal dichalcogenides (TMDs), which simultaneously increases the switching ratio and reduces the SET power. The SET voltage, SET power, switching ratio and endurance of the device are strongly correlated with rg. When the ratio of rg to the radius of the metal ions that form the conductive filaments (rg/rAg+) is near 1, the SET voltage and SET power vertically decrease while the switching ratio vertically rises with increasing rg/rAg+. For the fabricated Ag/[SnS2/poly(methyl methacrylate)]/Cu RRAM with an rg/rAg+ of 1.04, the SET voltage, SET power and switching ratio are 0.14 V, 10-10 W and 106, respectively. After 104 switching cycles and a 104 s retention time, the switching ratio of the device can still be stable above 106. Bending has no influence on the performance of the device when the bending radius is not <2 mm.

Ceftazidime-avibactam in the treatment of infections from carbapenem-resistant Klebsiella pneumoniae: Ceftazidime-avibactam against CR-KP infections.

OBJECTIVES: Clinical experience with ceftazidime-avibactam (CAZ-AVI) for the treatment of carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections is not well evaluated. The aim of this study was to assess its efficacy in a single-centre cohort of patients infected with CR-KP. METHODS: We conducted a retrospective observational study of consecutive patients treated for >72 h with CAZ-AVI or other active antibiotics (OAAs) for CR-KP infections. The primary outcome was 30-d mortality. The secondary outcomes were 14-d clinical failure and 14-d microbiological failure. Multivariate regression and propensity score matching were used to evaluate the relationship between CAZ-AVI treatment and outcomes. RESULTS: Ninety infections caused by CR-KP were documented in our study. Forty-two patients were treated with CAZ-AVI and 48 with OAAs. The crude 30-d mortality (8/42 vs. 22/48, P=0.007), 14-d clinical failure (14/42 vs. 24/48, P=0.046) and 14-d microbiological failure (11/42 vs. 15/48, P=0.034) were significantly lower in patients with CAZ-AVI treatment. The Kaplan-Meier survival curves of 30-d mortality confirmed the findings (logrank=0.004). In the multivariable models, the odds ratio (OR) of 30-d mortality (OR 0.23 95% CI 0.10-0.51, P<0.000), 14-d clinical failure (OR 0.37, 95% CI 0.14-0.95, P=0.039) and 14-d microbiological failure (OR 0.17, 95% CI 0.08-0.93, P=0.038) remain consistently significant. In the subgroup analysis, CAZ-AVI was associated with decreased 30-d mortality in the positive blood culture (OR 0.23, 95% CI 0.08-0.63, P=0.004), septic shock (OR 0.23, 95% CI 0.07-0.78, P=0.019), SOFA score (>5, OR 0.13, 95% CI 0.04-0.36, P<0.000), mechanical ventilation (OR 0.13, 95% CI 0.04-0.36, p<0.000) and Charlson comorbidity index (>3, OR 0.15, 95% CI 0.04-0.55, P=0.004). After propensity score matching, 29 cases from each group were well matched. The 30-d mortality remained significantly lower in the CAZ-AVI group (6/29 vs. 13/29, P=0.05). CONCLUSION: CAZ-AVI may be a more valuable therapeutic option for severe CR-KP infections than for mild cases and further randomized controlled trials are needed to evaluate the efficacy.

Genotypes of informative loci from 1000 Genomes data allude evolution and mixing of human populations.

Principal Component Analysis (PCA) projects high-dimensional genotype data into a few components that discern populations. Ancestry Informative Markers (AIMs) are a small subset of SNPs capable of distinguishing populations. We integrate these two approaches by proposing an algorithm to identify necessary informative loci whose removal from the data deteriorates the PCA structure. Unlike classical AIMs, necessary informative loci densely cover the genome, hence can illuminate the evolution and mixing history of populations. We conduct a comprehensive analysis to the genotype data of the 1000 Genomes Project using necessary informative loci. Projections along the top seven principal components demarcate populations at distinct geographic levels. Millions of necessary informative loci along each PC are identified. Population identities along each PC are approximately determined by weighted sums of minor (or major) alleles over the informative loci. Variations of allele frequencies are aligned with the history and direction of population evolution. The population distribution of projections along the top three PCs is recapitulated by a simple demographic model based on several waves of founder population separation and mixing. Informative loci possess locational concentration in the genome and functional enrichment. Genes at two hot spots encompassing dense PC 7 informative loci exhibit differential expressions among European populations. The mosaic of local ancestry in the genome of a mixed descendant from multiple populations can be inferred from partial PCA projections of informative loci. Finally, informative loci derived from the 1000 Genomes data well predict the projections of an independent genotype data of South Asians. These results demonstrate the utility and relevance of informative loci to investigate human evolution.

Treatment of a case presenting as critical adenoviral ARDS using Cidofovir with early combinatorial prone ventilation and ECMO.

Here, we report a case of adenoviral pneumonia associated with critical ARDS treated with Cidofovir, prone ventilation and extracorporeal membrane oxygenation (ECMO). The patient responded well to therapy and recovered without further complications. Cidofovir, with early prone ventilation and ECMO support, may be a therapeutic option for patients with critical ARDS related to adenoviral pneumonia.

The roles of MASPIN expression and subcellular localization in non-small cell lung cancer.

Accumulating studies have confirmed that mammary serine protease inhibitor (MASPIN) plays an essential role in non-small cell lung cancer (NSCLC). However, results are still controversial or inconsistent. In the present study, we attempted to identify the clinical significance of MASPIN and its potential molecular roles in NSCLC. The correlation of MASPIN with prognosis and clinicopathological characteristics was assessed by meta-analysis. Additionally, the potential molecular mechanisms of MASPIN in NSCLC was also investigated through several online databases. A total of 2220 NSCLC patients from 12 high quality studies were included and the results indicated that up-regulated MASPIN nucleus and cytoplasm expression was associated with poor overall survival (OS) (hazard ratio (HR) = 1.43, 95% confidence interval (CI) = 1.01-2.04, P<0.05), elevated MASPIN cytoplasm expression was associated with poor OS (HR = 1.45, 95% CI = 1.01-2.07, P<0.05), disease-free survival (DFS) (HR = 1.95, 95% CI = 1.31-2.88, P=0.001), and disease-specific survival (DSS) (HR = 2.17, 95% CI = 1.18-3.99, P=0.013). MASPIN both nucleus and cytoplasm location were associated with clinicopathological characteristics. Bioinformatics analysis validated the above results and suggested that human serpin family B member 5 (SERPINB5) hypomethylated levels were negatively correlated with its mRNA expression. Bioinformatics analysis also revealed the 85 most frequently altered neighboring genes of SERPINB5, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed 20 GO terms and 3 KEGG pathways with statistical significance. MASPIN had a statistically negative correlation with NSCLC prognosis, functioning as an oncoprotein by hypomethylation and influencing specific pathways involving the 85 genes identified herein. MASPIN might be a promising prognostic signature in NSCLC.