ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (+/- 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 296 evaluable patients (148 per arm) will provide statistical power of 90.5% to detect an 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse effects. Biospecimens including archival tumor tissue, plasma and buffy coat in EDTA tubes, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Discussion: Building off of data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed the current trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial Registration: Clinicaltrials.gov ID: NCT05610163 ; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

MicroRNAs in hepatocellular carcinoma treatment: Charting the path forward.

MicroRNAs (miRNAs) are recognized for their involvement in the regulation of gene expression and exhibit significant potential in both the prognostic assessment and treatment of hepatocellular carcinoma (HCC). HCC, like other tumors, seldom occurs in isolation; instead, it evolves within a microenvironment featuring oncogenic and tumor-suppressive elements. When combined with suitable delivery vehicles, miRNA technology provides the capability to directly engage with these elements, thereby hindering tumor formation and progression. Ongoing research in this domain holds the promise of enabling a more efficacious and multi-modal treatment approach for HCC in the near future.

[Analysis of safety and efficacy of laparoscopic surgery for gallbladder carcinoma].

Objective: To examine the efficacy and safety of laparoscopic surgery for gallbladder carcinoma. Methods: The data of 197 gallbladder carcinoma patients admitted at Peking Union Medical College Hospital between January 2012 and September 2022 were analyzed retrospectively. There were 86 males and 111 females,with age of (64.4±9.8)years(range:35 to 89 years). Patients were divided into laparoscopic group(n=53) and open group(n=144) according to different surgical methods. The general information of the two groups were matched by propensity score matching,and the clinical data and prognosis were compared between the two groups. Categorical variables were analyzed using χ2 test or Fisher's exact test,as appropriate. Continuous variables with and without normal distribution were analyzed using t-test and Mann-Whitney U test,respectively. Kaplan-Meier curves with Log-rank test were used to analyze the cumulative survival rates. Results: Forty-eight pairs of patients were matched successfully. There was no difference in general information,cholecystolithiasis,partial hepatectomy,and tumor stage between two groups(all P>0.05). The laparoscopic group had shorter operation time(t=-3.987,P<0.01),less bleeding(Z=-4.862,P<0.01),shorter total(Z=-5.009,P<0.01) and postoperative(Z=-5.412,P<0.01) hospital stay. Seventeen patients had postoperative complications. According to the Clavien-Dindo system,there were 4,11,1,and 1 patient with grade Ⅰ,Ⅱ,Ⅲa,and Ⅲb,respectively. All complications were improved after active treatment. After a median follow-up of 24(36) months(range:3 to 130 months),56 patients(58.3%) survived without tumor,7 patients(7.3%) survived with tumor,and 33 patients(34.4%) died. According to the Kaplan-Meier curves,there was no significant difference between laparoscopic and open groups in disease free(χ2=0.399,P=0.528) and overall(χ2=0.672,P=0.412) survival rates. Conclusions: The laparoscopic surgery is safe and effective in selected patients with gallbladder carcinoma. It can reduce surgical trauma and enhance patient recovery without increasing complication. Its prognosis is similar to that of open surgery.

Marked Improvement in Soft Tissue and CNS Manifestations of Adult Langerhans Cell Histiocytosis on Targeted MEK Inhibitor Therapy.

Multiple trials have demonstrated the efficacy of therapies targeting the RAS/MAPK pathway in children with Langerhans cell histiocytosis (LCH), but less is known about the success of this strategy in adults or in LCH that is the result of mutations other than BRAF V600E. A 53-year-old woman who has never smoked presented to our clinic with multisystem, multifocal LCH that resulted from an uncommon BRAF N486_P490del mutation. Low dose, and even intermittent, MEK inhibitor (trametinib) therapy was associated with rapid improvement in almost all of her disease manifestations, including regression of masses in her groin and neck, reduction in seizure frequency and intensity, improvement in white matter lesions on MRI, diabetes insipidus, dyspnea, and cognitive and memory functions. We conclude that MEK inhibitor therapy was effective for BRAF mutation-associated adult multisystem LCH, including CNS manifestations, in this patient.

[Application of enhanced recovery after surgery in perioperative management of patients with gallbladder carcinoma].

Objective: To investigate the efficacy and safety of enhanced recovery after surgery (ERAS) in perioperative management of patients with gallbladder carcinoma. Methods: The data of the patients with gallbladder carcinoma admitted at Peking Union Medical College Hospital between January 2017 and December 2021 were analyzed retrospectively. There were 69 males(42.1%) and 95 females(57.9%),with age of (64.0±10.3) years(range:37 to 89 years). Patients were divided into ERAS group(n=53) and normal group(n=111) according to whether they were treated with ERAS measures during the perioperative period.The basic characteristics of the two groups were matched by propensity score matching,and then the perioperative information was compared between the two groups. Categorical variables were presented as absolute numbers or frequencies. Differences between study groups were analyzed using χ2 test, Fisher's exact test, t-test, or Mann-Whitney U test, as appropriate. Results: Each group had 45 patients after propensity score matching with well-balanced basic characteristics. There was no difference in basic characteristics, operation time,bleeding,complication,and hospitalization expenses between two groups(all P>0.05). Compared with the normal group,time of ambulation (M(IQR)) (1(1) day vs. 2(2) days;Z=-3.839,P<0.01),postoperative anal exhaust time (2(1) days vs. 3(1) days;Z=-3.013,P=0.003),feeding time(2(1) days vs. 2(1) days;Z=-3.647,P<0.01),postoperative (5(2) days vs. 7(4) days;Z=-3.984,P<0.01) and total(8(4) days vs. 13(6) days;Z=-3.605,P<0.01) hospitalization time were shorter in ERAS group. Postoperative complications occurred in 12 patients. According to the Clavien-Dindo classification,6,4,and 2 patients were classified as grade Ⅰ,Ⅱ,and Ⅲa,respectively. Conclusion: The ERAS measures is safe and effective for perioperative management of patients with gallbladder carcinoma, enhancing patient recovery and shortening hospitalization time without increasing complication or hospitalization cost.

Anti-Inflammatory Effect of Licochalcone A via Regulation of ORAI1 and K+ Channels in T-Lymphocytes.

Calcium signaling plays a vital role in the regulation of various cellular processes, including activation, proliferation, and differentiation of T-lymphocytes, which is mediated by ORAI1 and potassium (K+) channels. These channels have also been identified as highly attractive therapeutic targets for immune-related diseases. Licochalcone A is a licorice-derived chalconoid known for its multifaceted beneficial effects in pharmacological treatments, including its anti-inflammatory, anti-asthmatic, antioxidant, antimicrobial, and antitumorigenic properties. However, its anti-inflammatory effects involving ion channels in lymphocytes remain unclear. Thus, the present study aimed to investigate whether licochalcone A inhibits ORAI1 and K+ channels in T-lymphocytes. Our results indicated that licochalcone A suppressed all three channels (ORAI1, Kv1.3, and KCa3.1) in a concentration-dependent matter, with IC50 values of 2.97 ± 1.217 µM, 0.83 ± 1.222 µM, and 11.21 ± 1.07 µM, respectively. Of note, licochalcone A exerted its suppressive effects on the IL-2 secretion and proliferation in CD3 and CD28 antibody-induced T-cells. These results indicate that the use of licochalcone A may provide an effective treatment strategy for inflammation-related immune diseases.

Type 2 diabetes mellitus duration and obesity alter the efficacy of autologously transplanted bone marrow-derived mesenchymal stem/stromal cells.

Human bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) represent promising stem cell therapy for the treatment of type 2 diabetes mellitus (T2DM), but the results of autologous BM-MSC administration in T2DM patients are contradictory. The purpose of this study was to test the hypothesis that autologous BM-MSC administration in T2DM patient is safe and that the efficacy of the treatment is dependant on the quality of the autologous BM-MSC population and administration routes. T2DM patients were enrolled, randomly assigned (1:1) by a computer-based system into the intravenous and dorsal pancreatic arterial groups. The safety was assessed in all the treated patients, and the efficacy was evaluated based on the absolute changes in the hemoglobin A1c, fasting blood glucose, and C-peptide levels throughout the 12-month follow-up. Our data indicated that autologous BM-MSC administration was well tolerated in 30 T2DM patients. Short-term therapeutic effects were observed in patients with T2DM duration of <10 years and a body mass index <23, which is in line with the phenotypic analysis of the autologous BM-MSC population. T2DM duration directly altered the proliferation rate of BM-MSCs, abrogated the glycolysis and mitochondria respiration of BM-MSCs, and induced the accumulation of mitochondria DNA mutation. Our data suggest that autologous administration of BM-MSCs in the treatment of T2DM should be performed in patients with T2DM duration <10 years and no obesity. Prior to further confirming the effects of T2DM on BM-MSC biology, future work with a larger cohort focusing on patients with different T2DM history is needed to understand the mechanism underlying our observation.

[Mechanism of advanced glycation end products inhibiting the proliferation of peripheral blood mononuclear cells and osteoblasts in rats].

OBJECTIVE: To explore the mechanism of nuclear factor-kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/protein kinase B(PKB/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways after intervention of advanced glycosylation end products (AGEs) in peripheral blood mononuclear cells (PBMCs) and osteoblasts (OB) in rats, so as to provide certain experimental basis and theoretical basis for further research on the clinical treatment of periodontal tissue inflammation caused by diabetes mellitus. METHODS: AGEs were prepared, PBMCs and OB were isolated and cultured in vitro. CCK-8 was used to detect the cell viability intervened by different concentrations and time of AGEs. Western blot and qRT-PCR were used to detect the expression changes of genes related to NF-κB, PI3K/PKB and MAPK signaling pathways. RESULTS: OB and PBMCs were successfully isolated and cultured in vitro. The activity of PBMCs and OB cells was significantly correlated with the concentration, time and interaction of AGEs. With the increase of AGEs concentration and time, the activity of PBMCs and OB cells significantly decreased (P < 0.001). AGEs stimulation significantly increased the expression of NF-κB in PBMCs and the contents of tumor necrosis factor α(TNF-α), interleukin-1ß(IL-1ß) (P < 0.01). TNF-α, IL-1ß levels were significantly reduced after inhibition of NF-κB pathway (P < 0.01). NF-κB p65, JNK, and p38 phosphorylated and non-phosphorylated proteins increased significantly after AGEs stimulation of OB (P < 0.05). The phosphorylated protein expression of IκB was significantly increased, while the expression of non-phosphorylated protein was decreased (P < 0.01).The expressions of NF-κB p65, JNK, and IκB were significantly increased at the mRNA levels, and the expressions of IκB mRNA were significantly decreased (P < 0.05). There was no difference in the expression of Akt in either phosphorylated or non-phosphorylated proteins or at the mRNA level (P>0.05). With the addition of MAPK signaling pathway inhibitors, the phosphorylation and non-phosphorylated protein expressions of NF-κB p65, p38 and JNK were significantly reduced, and the phosphorylated protein of IκB was significantly decreased and the non-phosphorylated protein was significantly increased compared with the group with AGEs alone (P < 0.05). The results of qRT-PCR showed that the expression of IκB increased significantly after the addition of the JNK pathway blocker (P < 0.05), and the expression of NF-κB p65, p38 and JNK decreased, but the difference was not significant (P>0.05). While NF-κB p65, p38 and JNK were significantly decreased and IκB was significantly increased in the AGEs group after the addition of the p38 pathway blocker (P < 0.05). At this time, there was still no significant change in the expression of Akt at the protein level and mRNA level (P>0.05). CONCLUSION: AGEs inhibit the proliferation of PBMCs and OB, and the NF-κB and MAPK pathways are likely involved in regulating this process, but not the PI3K/PKB pathway.

Endoscopic endonasal resection of coexisting pituitary adenoma and meningioma: Two cases' report and literature review.

INTRODUCTION: The coexistence of pituitary adenoma (PA) and para/suprasellar meningioma is an extremely rare event, which generally occurs in previous case reports. Literature on the endonasal endoscopic approach (EEA) to treat such synchronous tumours remains sparse. CASE DESCRIPTION: Two cases of concomitant sellar and supra/parasellar tumours are reported. A 62-year-old woman with a PA and a tuberculum sellae meningioma and a 56-year-old woman with a PA and a cavernous sinus (CS) meningioma. Both coexisting tumours were resected through a single extended EEA and achieved a good prognosis. To the best of our knowledge, endoscopic endonasal resection of coexisting PA and CS meningioma has not been previously reported in the literature. CONCLUSION: Our reports add to the literature two cases of coexisting PA and meningioma, with different consistence in sellar and para/suprasellar regions. Furthermore, the present case adds to the evidence that in the rare situation of coexisting sellar and suprasellar tumours located in the same sagittal plane, an extended EEA allows adequate exposure and safe removal of both tumours. However, for tumours coexisting in the sellar and parasellar region in the same coronal plane, we should draw attention to this rare situation for differential diagnosis of synchronous PA and CS meningioma to avoid unnecessary surgery and to decide the best strategy for treatment.

Gastric Adenocarcinoma Arising in Gastrocystoplasty.

Gastric cancer is a rare long-term complication in gastrocystoplasty. We report 2 cases of gastric adenocarcinoma and review the literature for similar cases. A total of 14 cases are identified. The majority of patients are males, presented with hematuria, and developed cancer at a younger age, more than 10 years after gastrocystoplasty. Long-term follow up information was limited, but 5 patients (36%) died within 5 years of diagnosis. Annual surveillance for malignancy may not be effective due to its rarity. However, symptomatic patients, particularly those 10 years after the surgery, warrant detailed evaluation to rule out neoplastic transformation.

Microstructural, Tribology and Corrosion Properties of Optimized Fe3O4-SiC Reinforced Aluminum Matrix Hybrid Nano Filler Composite Fabricated through Powder Metallurgy Method.

Hybrid reinforcement's novel composite (Al-Fe3O4-SiC) via powder metallurgy method was successfully fabricated. In this study, the aim was to define the influence of SiC-Fe3O4 nanoparticles on microstructure, mechanical, tribology, and corrosion properties of the composite. Various researchers confirmed that aluminum matrix composite (AMC) is an excellent multifunctional lightweight material with remarkable properties. However, to improve the wear resistance in high-performance tribological application, hardening and developing corrosion resistance was needed; thus, an optimized hybrid reinforcement of particulates (SiC-Fe3O4) into an aluminum matrix was explored. Based on obtained results, the density and hardness were 2.69 g/cm3, 91 HV for Al-30Fe3O4-20SiC, after the sintering process. Coefficient of friction (COF) was decreased after adding Fe3O4 and SiC hybrid composite in tribology behaviors, and the lowest COF was 0.412 for Al-30Fe3O4-20SiC. The corrosion protection efficiency increased from 88.07%, 90.91%, and 99.83% for Al-30Fe3O4, Al-15Fe3O4-30SiC, and Al-30Fe3O4-20SiC samples, respectively. Hence, the addition of this reinforcement (Al-Fe3O4-SiC) to the composite shows a positive outcome toward corrosion resistance (lower corrosion rate), in order to increase the durability and life span of material during operation. The accomplished results indicated that, by increasing the weight percentage of SiC-Fe3O4, it had improved the mechanical properties, tribology, and corrosion resistance in aluminum matrix. After comparing all samples, we then selected Al-30Fe3O4-20SiC as an optimized composite.

Flavin-Dependent Monooxygenases NotI and NotI' Mediate Spiro-Oxindole Formation in Biosynthesis of the Notoamides.

The fungal indole alkaloids are a unique class of complex molecules that have a characteristic bicyclo[2.2.2]diazaoctane ring and frequently contain a spiro-oxindole moiety. While various strains produce these compounds, an intriguing case involves the formation of individual antipodes by two unique species of fungi in the generation of the potent anticancer agents (+)- and (-)-notoamide A. NotI and NotI' have been characterized as flavin-dependent monooxygenases that catalyze epoxidation and semi-pinacol rearrangement to form the spiro-oxindole center within these molecules. This work elucidates a key step in the biosynthesis of the notoamides and provides an evolutionary hypothesis regarding a common ancestor for production of enantiopure notoamides.

Comparison of pegylated liposomal doxorubicin and paclitaxel plus carboplatin-based chemotherapy as first line treatment for patients with ovarian cancer: a systematic review and meta-analysis of randomized controlled trials.

We reviewed studies comparing survival outcomes such as overall survival (OS), progression free survival (PFS), and toxicity profile between patients treated with Pegylated Liposomal Doxorubicin (PLD) combination and those treated with paclitaxel combination for ovarian cancer. We conducted systematic searches in various databases including Medline, Cochrane Controlled Register of Trials (CENTRAL), ScienceDirect, and Google Scholar from inception until August 2019. We used the Cochrane risk of bias tool to assess the quality of published trials. We carried out a meta-analysis with random-effects model and reported pooled Hazard ratios (HR) or Risk ratios (RR) with 95% confidence intervals (CIs). In total, we analysed 7 studies including 3,676 participants. All the studies were randomized controlled trials, while majority of studies had low bias risks. We did not find significant evidence for any of these outcomes except progression free survival (favoured PLD combination therapy pooled HR=0.87; 95% CI: 0.77-0.98). Worst grade toxicities like allergy (pooled RR: 1.86; 95% CI: 1.06-3.24) and neurotoxicity (pooled RR: 5.59; 95% CI: 1.43-21.84) were significantly higher among patients receiving paclitaxel combination therapy when compared to patients receiving PLD combination therapy. To summarize, PLD combination therapy is non-inferior to paclitaxel combination therapy in the management of ovarian cancer with respect to survival outcomes and worst grade toxicity profile. However, clinical recommendations cannot be made, as the evidence is not conclusive or significant enough.

Efficient electrochemical generation of ferrate(VI) by iron coil anode imposed with square alternating current and treatment of antibiotics.

Anode passivation is still a main challenge for the electrochemical generation of ferrate(VI, Fe(VI)), leading to the reduction of Fe(VI) production efficiency. In this study, cyclic voltammetry, scanning electronic microscopy, and electrochemical impedance spectroscopy were used to select better anode electrode configurations (iron wire, iron gauze, and iron coil). The results indicate that iron coil had the least degree of passivation. Different imposed current waveforms during the electrochemical generation of Fe(VI) were also investigated, and the iron coil imposed with square alternating current (AC) wave can mitigate the anode passivation, resulting in higher Fe(VI) production efficiency. The optimum conditions for the electrochemical generation of Fe(VI) were evaluated and the optimum temperature (40 ℃), current density (10 mA/cm2), AC cycle period (15 s) and electrolyte concentrations (14 M NaOH) were identified. As a result, 0.12 mol/L Fe(VI) concentration and over 50% of current efficiency can be achieved after 3 h electrolysis. The generated Fe(VI) solution was further applied to oxidize doxycycline(DOX) and sulfadiazine(SDZ) as typical antibiotics. Over 80% of DOX can be removed at a Fe(VI) to DOX molar ratio of 5:1 (pH = 4-9), whilst a higher Fe(VI) to SDZ molar ratio of 20:1 (pH = 7) was needed to obtain 75% SDZ removal.

Macrolide-Resistant Mycoplasma pneumoniae in the United States as Determined from a National Surveillance Program.

There are sparse data to indicate the extent that macrolide-resistant Mycoplasma pneumoniae (MRMp) occurs in the United States or its clinical significance. Between 2015 and 2018, hospitals in 8 states collected and stored respiratory specimens that tested positive for M. pneumoniae and sent them to the University of Alabama at Birmingham, where real-time PCR was performed for detection of 23S rRNA mutations known to confer macrolide resistance. MRMp was detected in 27 of 360 specimens (7.5%). MRMp prevalence was significantly higher in the South and East (18.3%) than in the West (2.1%). A2063G was the predominant 23S rRNA mutation detected. MICs for macrolide-susceptible M. pneumoniae (MSMp) were ≤0.008 µg/ml, whereas MICs for MRMp were 16 to 32 µg/ml. Patients with MRMp infection were more likely to have a history of immunodeficiency or malignancy. Otherwise, there were no other significant differences in the clinical features between patients infected with MRMp and those infected with MSMp, nor were there any differences in radiographic findings, hospitalization rates, viral coinfections, the mean duration of antimicrobial treatment, or clinical outcomes. There was no significant change in MRMp incidence over time or according to age, sex, race/ethnicity, or status as an inpatient or an outpatient. Patients with MRMp were more likely to have received a macrolide prior to presentation, and their treatment was more likely to have been changed to a fluoroquinolone after presentation. This is the first national surveillance program for M. pneumoniae in the United States. Additional surveillance is needed to assess the clinical significance of MRMp and to monitor changes in MRMp prevalence.

[The etiological analysis of 260 hospitalized cases with bilateral adrenal lesions].

Objective: To summarize the etiologies of bilateral adrenal lesions and the changes of the disease profile in hospitalized patients. Methods: Bilateral adrenal lesion screening was conducted in all patients admitted to Peking University Third Hospital from 1994 to 2017. The etiologies and disease profiles of bilateral adrenal lesions were retrospectively analyzed. Results: A total of 260 patients with bilateral adrenal lesions were included in the study. There were 146 males and 114 females with a mean age of (55.4±16.2) years. The most common adrenal lesion was bilateral adrenal hyperplasia (75 cases, 28.8%), followed by bilateral adrenal adenomas (71 cases, 27.3%), metastatic carcinoma (51 cases, 19.6%), discordant bilateral adrenal lesions (27 cases, 10.4%), bilateral pheochromocytomas (13 cases, 5.0%), and others. The clear data of endocrine function evaluation could be found in 184 patients. Among them, 111 cases (60.3%) were nonfunctioning lessions, 34 cases (18.5%) with primary aldosteronism, 15 cases (8.1%) with pheochromocytoma, 13 cases (7.1%) with congenital adrenal hyperplasia, 6 cases (3.3%) with primary hypoadrenocorticism, and 5 cases (2.7%) with Cushing syndrome. Using every 8 years as a period of time, the number of hospitalized patients with bilateral adrenal lesions increased with years in three periods (8, 41 and 211 cases, respectively). Conclusions: The most common cause of bilateral adrenal lesions is adrenal hyperplasia in the hospitalized patients. More than half of bilateral adrenal lesions are nonfunctioning. In functional bilateral lesions, primary aldosteronism and pheochromocytoma account for a large proportion.

Klebsiella pneumoniae disassembles host microtubules in lung epithelial cells.

Klebsiella pneumoniae raises significant concerns to the health care industry as these microbes are the source of widespread contamination of medical equipment, cause pneumonia as well as other multiorgan metastatic infections and have gained multidrug resistance. Despite soaring mortality rates, the host cell alterations occurring during these infections remain poorly understood. Here, we show that during in vitro and in vivo K. pneumoniae infections of lung epithelia, microtubules are severed and then eliminated. This destruction does not require direct association of K. pneumoniae with the host cells, as microtubules are disassembled in cells that are distant from the infecting bacteria. This microtubule dismantling is dependent on the K. pneumoniae (Kp) gene ytfL as non-pathogenic Escherichia coli expressing Kp ytfL disassemble microtubules in the absence of K. pneumoniae itself. Our data points to the host katanin catalytic subunit A like 1 protein (KATNAL1) and the katanin regulatory subunit B1 protein (KATNB1) as the gatekeepers to the microtubule severing event as both proteins localise specifically to microtubule cut sites. Infected cells that had either of these proteins knocked out maintained intact microtubules. Taken together, we have identified a novel mechanism that a bacterial pathogen has exploited to cause microtubule destruction within the host epithelia.

Immune Stimulation Using a Gut Microbe-Based Immunotherapy Reduces Disease Pathology and Improves Barrier Function in Ulcerative Colitis.

Background: Current ulcerative colitis (UC) treatments are focused on symptom management primarily via immune suppression. Despite the current arsenal of immunosuppressant treatments, the majority of patients with UC still experience disease progression. Importantly, aggressive long-term inhibition of immune function comes with consequent risk, such as serious infections and malignancy. There is thus a recognized need for new, safe and effective treatment strategies for people living with UC that work upstream of managing the symptoms of the disease. The objective of this study was to evaluate a microbial-based treatment, QBECO, that functions to productively activate rather than suppress mucosal immune function as a novel approach to treat UC. Methods: Two established models of experimental colitis, namely chemically-induced DSS colitis and the spontaneous colitis that develops in Muc2 deficient mice, were used to assess whether QBECO treatment could ameliorate gastrointestinal disease. A small exploratory 16-week QBECO open-label trial was subsequently conducted to test the safety and tolerability of this approach and also to determine whether similar improvements in clinical disease and histopathology could be demonstrated in patients with moderate-to-severe UC. Results: QBECO treatment successfully reduced inflammation and promoted mucosal and histological healing in both experimental models and in UC patients. The preclinical models of colitis showed that QBECO ameliorated mucosal pathology, in part by reducing inflammatory cell infiltration, primarily that induced by neutrophils and inflammatory T cells. The most rapid and noticeable change observed in QBECO treated UC patients was a marked reduction in rectal bleeding. Conclusion: Collectively, this work demonstrates for the first time that strategically activating immune function rather than suppressing it, not only does not worsen colitis induced-damage, but may lead to an objective reduction in UC disease pathology.

Research on ketamine in mediating autophagy and inhibiting apoptosis of astrocytes in cerebral cortex of rats through NF-κB pathway.

OBJECTIVE: To investigate the effects of ketamine on autophagy and apoptosis of astrocytes in the cerebral cortex of rats, and determine whether nuclear factor-κB (NF-κB) pathway is involved in the regulation of autophagy and apoptosis of astrocytes. MATERIALS AND METHODS: A total of 36 male Sprague-Dawley (SD) rats were randomly divided into 3 groups: control group (Group C: intraperitoneal injection of equal amount of normal saline), glutamic acid group (Group G: intraperitoneal injection of 1 mg/kg glutamic acid) and glutamic acid + ketamine group (Group GK: intraperitoneal injection of 1 mg/kg glutamic acid and then injection of 5 mg/kg ketamine after 30 min). The cerebral cortex of rats in each group was taken after successive administration for 5 d. The number of glial fibrillary acidic protein (GFAP)-positive cells in the cerebral cortex of rats in each group was detected via immunofluorescence. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells (apoptotic cells) in the cerebral cortex was detected via TUNEL staining. The levels of inflammatory factors were detected using the enzyme-linked immunosorbent assay (ELISA) kit. Moreover, the expressions of autophagy-related proteins and apoptosis-related proteins in the cerebral cortex were detected via Western blotting, and the expressions of IκB-a and NF-κBp65 were also detected. RESULTS: The results of immunofluorescence showed that the number of GFAP-positive cells in the cerebral cortex of rats in Group G was significantly increased compared with that in Group C (p<0.01), and it was significantly decreased in Group GK compared with that in Group G (p<0.01). The results of TUNEL staining revealed that the number of TUNEL-positive cells in the cerebral cortex in Group G was significantly larger than that in Group C, and it was significantly smaller in Group GK than that in Group G (p<0.01). Results of ELISA demonstrated that compared with those in Group C, the contents of interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) in Group G were significantly increased (p<0.01), but the content of IL-10 was significantly decreased (p<0.01). Compared with those in Group G, the contents of IL-6 and TNF-a in Group GK were significantly decreased (p<0.01), but the level of IL-10 was statistically elevated (p<0.01). Compared with those in Group C, the levels of LC3 II/I and cleaved caspase-3 in the cerebral cortex in Group G were significantly increased (p<0.01), but the p62 level and B-cell lymphoma-2/Bcl-2 associated X protein (Bcl-2/Bax) ratio were significantly decreased (p<0.01). In Group GK, the levels of LC3 II/I and cleaved caspase-3 were reduced, but the p62 level and Bcl-2/Bax ratio were increased. The expressions of IκB-α and NF-κBp65 in Group G were significantly decreased compared with those in Group C (p<0.01), and they were significantly higher in Group GK than those in Group G (p<0.01). CONCLUSIONS: Ketamine can reduce the glutamic acid-induced activation of astrocytes in the cerebral cortex, inhibit the autophagy and alleviate the apoptosis of astrocytes, the process of which is mediated by the NF-κB pathway, which provides the new molecular basis of ketamine in protecting astrocytes.