Harnessing CD8+ T-cell exhaustion to treat type 1 diabetes.

Although immune interventions have shown great promise in type 1 diabetes mellitus (T1D) clinical trials, none are yet in routine clinical use or able to achieve insulin independence in patients. In addition to this, the principles of T1D treatment remain essentially unchanged since the isolation of insulin, almost a century ago. T1D is characterized by insulin deficiency as a result of destruction of insulin-producing beta cells mediated by autoreactive T cells. Therapies that target beta-cell antigen-specific T cells are needed to prevent T1D. CD8+ T-cell exhaustion is an emerging area of research in chronic infection, cancer immunotherapy, and more recently, autoimmunity. Recent data suggest that exhausted T-cell populations are associated with improved markers of T1D. T-cell exhaustion is both characterized and mediated by inhibitory receptors. This review aims to identify which inhibitory receptors may prove useful to induce T-cell exhaustion to treat T1D and identify limitations and gaps in the current literature.

The impact of new systemic therapies on survival and time on hormonal treatment in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: A population-based study in British Columbia from 2003 to 2013.

BACKGROUND: The purpose of this study was to determine whether new systemic therapy regimens have resulted in improved survival and increased time on first- and second-line hormonal treatment for patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) over time. METHODS: Patients diagnosed with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC were identified across 3 time cohorts (2003-2005, 2007-2009, and 2011-2013). Data were prospectively collected. Cases with previous, synchronous, or subsequent contralateral breast cancer were excluded. The types of first- and second-line therapies, the times on first- and second-line hormonal treatment, and the median survival times were compared across the cohorts. RESULTS: Within the time period analyzed, 9 new adjuvant systemic therapies (with or without neoadjuvant therapy) and 2 metastatic systemic therapies were approved at BC Cancer for the treatment of HR-positive, HER2-negative MBC. In the 3 time cohorts, 3953 patients diagnosed with MBC were identified. Among the 2432 patients (62%) who had HR-positive/HER2-negative disease, 2197 (90%) received at least 1 line of systemic therapy after the diagnosis of MBC, and 80% of these patients (1752 of 2197) received first- and/or second-line hormonal treatment. The median duration on hormonal treatment was 9.0 months for the first line and 6.1 months for the second line. The durations were similar across the time cohorts (range for the first line, 8.9-9.0 months; range for the second line, 6.0-6.1 months). The median survival for the entire study population was 2.0 years (95% confidence interval, 1.8-2.1 years), and there was no significant difference between the cohorts (range, 1.9-2.0 years). CONCLUSIONS: Even though more adjuvant and metastatic systemic therapies have been approved since 2003, population-level gains in survival and the time on hormonal treatment for patients with HR-positive, HER2-negative MBC have not been made over the course of a decade.

Impact of wait time from neoadjuvant chemotherapy to surgery in breast cancer: Does time to surgery affect patient outcomes? : Time from Neoadjuvant Chemotherapy to Surgery.

PURPOSE: The optimal time interval from neoadjuvant chemotherapy (NAC) to surgery in patients with breast cancer has not been established. We investigated whether different time intervals impact the rate of pathologic complete response (pCR), disease free survival (DFS), overall survival (OS), surgical complications, and rates of conversion from mastectomy to breast conserving surgery (BCS) in this population. METHODS: We identified patients who received NAC at the BC Cancer Agency followed by surgery from May 2012 to April 2018. Patients were grouped based on time interval between NAC and surgery: < 4 weeks, 4-8 weeks, and > 8 weeks. Kaplan Meier method was used to estimate DFS and OS. Rates of pCR between the time intervals were also compared. RESULTS: Of the 343 patients, 78 (22.8%) received surgery < 4 weeks, 233 (67.9%) received surgery between 4-8 weeks, and 32 (9.3%) received surgery > 8 weeks after NAC, with a median time to surgery (TTS) of 5.0 weeks. pCR was observed in 32.1%, 32.2%, and 28.1%, respectively (p = 0.90). Median follow-up time was 3.3 years. The 5-year DFS was 76%, 78%, and 70% (p = 0.89), respectively. The 5-year OS was 83%, 82%, and 78% (p = 0.33), respectively. No statistically significant differences were seen in surgical complications (p = 0.90), or rates of conversion from mastectomy to BCS (p = 0.19). CONCLUSIONS: There were no statistically significant differences in pCR, DFS, OS, surgical complications, and rates of conversion from mastectomy to BCS, among breast cancer patients receiving surgery < 4 weeks, 4-8 weeks, or > 8 weeks after the last dose of NAC.

Epidemiological features and viral shedding in children with SARS-CoV-2 infection.

A pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection broke out all over the world; however, epidemiological data and viral shedding in pediatric patients are limited. We conducted a retrospective, multicenter study, and followed-up with all children from the families with SARS-CoV-2 infected members in Zhejiang Province, China. All infections were confirmed by testing the SARS-CoV-2 RNA with real-time reverse transcription PCR method, and epidemiological data between children and adults in the same families were compared. Effect of antiviral therapy was evaluated observationally and fecal-viral excretion times among groups with different antiviral regiments were compared with Kaplan-Meier plot. By 29 February 2020, 1298 cases from 883 families were confirmed with SARS-CoV-2 infection and 314 of which were families with children. Incidence of infection in child close contacts was significantly lower than that in adult contacts (13.2% vs 21.2%). The mean age of 43 pediatric cases was 8.2 years and mean incubation period was 9.1 days. Forty (93.0%) were family clustering. Thirty-three children had coronavirus disease 2019 (20 pneumonia) with mild symptoms and 10 were asymptomatic. Fecal SARS-CoV-2 RNA detection was positive in 91.4% (32/35) cases and some children had viral excretion time over 70 days. Viral clearance time was not different among the groups treated with different antiviral regiments. No subsequent infection was observed in family contacts of fecal-viral-excreting children. Children have lower susceptibility of SARS-CoV-2 infection, longer incubation, and fecal-viral excretion time. Positive results of fecal SARS-CoV-2 RNA detection were not used as indication for hospitalization or quarantine.

Interventions to Promote Safety Culture in Cancer Care: A Systematic Review.

OBJECTIVES: There is limited guidance on how to effectively promote safety culture in health care settings. We performed a systematic review to identify interventions to promote safety culture, specifically in oncology settings. METHODS: Medical Subject Headings and text words for "safety culture" and "cancer care" were combined to conduct structured searches of MEDLINE, EMBASE, CDSR, CINAHL, Cochrane CENTRAL, PsycINFO, Scopus, and Web of Science for peer-reviewed articles published from 1999 to 2021. To be included, articles had to evaluate a safety culture intervention in an oncology setting using a randomized or nonrandomized, pre-post (controlled or uncontrolled), interrupted time series, or repeated-measures study design. The review followed PRISMA guidelines; quality of included citations was assessed using the ROBINS-I risk of bias tool. RESULTS: Eighteen articles meeting the inclusion criteria were retained, reporting on interventions in radiation (14 of 18), medical (3 of 18), or general oncology (1 of 18) settings. Articles most commonly addressed incident learning systems (7 of 18), lean initiatives (4 of 18), or quality improvement programs (3 of 18). Although 72% of studies reported improvement in safety culture, there was substantial heterogeneity in the evaluation approach; rates of reporting of adverse events (9 of 18) or Agency for Healthcare Research and Quality Safety Culture survey results (9 of 18) were the most commonly used metrics. Most of the studies had moderate (28%) or severe (67%) risk of bias. CONCLUSIONS: Despite a growing evidence base describing interventions to promote safety culture in cancer care, definitive recommendations were difficult to make because of heterogeneity in study designs and outcomes. Implementation of incident learning systems seems to hold most promise.

[Levonorgestrel-releasing intrauterine system and combined oral contraceptives as conservative treatments for recurrent ovarian endometriosis: a comparative clinical study].

OBJECTIVE: To evaluate and compare the efficiency and safety of levonorgestrel-releasing intrauterine system (LNG-IUS) and combined oral contraceptives (COC) in the treatment of recurrent ovarian endometriosis after conservative surgery or conservative surgery plus medical therapy. METHODS: A total of 48 patients with recurrent ovarian endometriosis underwent randomization. The regimens of LNG-IUS (n = 24) and COC (n = 24) were offered. The volume of ovarian endometriotic cysts was recorded before treatment and at 6, 12, 18 and 24 months. The volume of ovarian endometriotic cysts, pain score of visual analogue scale (VAS), menstrual pattern, body weight, serum CA125 and serum lipids were compared to the pretreatment level within each treatment group, as well as between two treatment groups during the same period. RESULTS: (1) At 18 months after LNG-IUS, the cysts in 2 subjects entirely disappeared. At 24 months, 18 patients had a disappearance of cysts. The overall size reduction was statistically significant (9.2 ± 3.0) vs (0.9 ± 1.5) cm(3) (P < 0.01). In the COC group, 12 subjects had a complete resolution of cysts at 24 months. The overall size reduction was statistically significant (9.4 ± 2.2) vs (2.9 ± 3.1) cm(3) (P < 0.01). At 18 & 24 months, the cyst size reduction was significantly larger in the LNG-INS group than the COC group (2.4 ± 1.5) vs (4.7 ± 2.6) cm(3) (P < 0.01) and (0.9 ± 1.5) vs (2.9 ± 3.1) cm(3) (P < 0.05); (2) There was a significant improvement of dysmenorrhea, chronic pelvic pain and dyspareunia at 6- & 12-month follow-up in both groups; (3) serum CA125 decreased at 6 & 12 months in both groups with statistical significance. It decreased more sharply in the LNG-IUS group and remained at low levels beyond 12 months; (4) within 6 months of LNS-IUS, irregular bleeding and spotting were the major side effects. Beyond that period the symptoms were significantly relieved. Weight gain and dyslipidemia were the major side effects of COC. CONCLUSION: For patients with recurrent ovarian endometriosis after conservative surgery or conservative surgery plus medical therapy, LNG-IUS and COC may be used to control and reduce endometriotic cysts, relieve pain and reduce the level of CA125. LNG-IUS has the advantages of a greater convenience and minor systemic side effects.

[Evaluation of levonorgestrel-releasing intrauterine system in treatment of recurrent endometriosis after conservative surgery].

OBJECTIVE: To evaluate the efficiency of levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment. METHODS: Twenty-three patients with recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment were treated by LNG-IUS. All patients rejected further operation and had no desire of fertility. The visual analogue scale (VAS) scores of pain, menstrual model, weight and serum CA125 level and the volume of ovarian endometriotic cysts before and after 3, 6, 12, 24 and 36 months of treatment were recorded and compared. RESULTS: (1) VAS score:after 12 months of using LNG-IUS, dysmenorrheal, chronic pelvic pain or dyspareunia were relieved significantly. VAS score were dropped from 5.9±2.3, 4.3±2.0 to 1.0±0.7, 1.4±1.1 (P<0.01). (2) Volum of cysts:after 6 months of using LNG-IUS, the volume of recurrent ovarian endometriotic cysts in 11 patients were reduced from (11.4±6.1) cm3 to (5.5±3.4) cm3 significantly (P<0.01). At 12 months of follow-up, it suggested that 2 patients' ovarian endometriotic cysts disappeared. At 24 months follow-up, 9 patients ovarian endometriotic cysts disappeared (3) CA125: serum CA125 decreased from (65.5±19.6) kU/L to (42.1±13.6) kU/L at 6 months after treatment remarkably (P<0.01). Continued to decrease after 12 months and then become steady. Irregular bleeding and spotting was the main side effects, weight gain was also observed in few patients. CONCLUSIONS: LNG-IUS could be used in treatment of recurrent endometriosis after conservative surgery or conservative surgery combined with medical treatment effectively. It could relieve pain, reduce the level of CA125 and decrease the size of ovarian endometriotic cysts. LNG-IUS seems to be an effective, safe, and long term treatment for endometriosis with fewer side effects and better compliance.

A Rare Case of Severe Lactic Acidosis from 5-Fluorouracil after mFOLFOX6 Treatment in a Patient with Advanced Gastric Cancer.

Gastric cancer is one of the most common cancers worldwide and is one of the deadliest types of neoplasm. Many patients present with an advanced stage where palliative chemotherapy is the standard of care. 5-Fluorouracil (5-FU) remains the backbone of systemic therapy treatment in advanced gastric cancer, although is associated with many side effects. While cases of encephalopathy caused by hyperammonemia have been reported, lactic acidosis after systemic 5-FU exposure is exceedingly rare. We present here for the first time a case of type B lactic acidosis secondary to mFOLFOX6 therapy in advanced gastric cancer. This patient presented with acute delirium, dystonia, and a lactate of 11.7 mmol/L, which peaked to 18.7 mmol/L, within 48 h of chemotherapy treatment. Routine clinical monitoring of lactate may be beneficial to avoid this potentially life-threatening adverse event.

Low-dose clozapine-related seizure: A case report and literature review.

BACKGROUND: Treatment-resistant schizophrenia is a severe form of schizophrenia characterized by poor response to at least two antipsychotic drugs and is typically treated with clozapine. However, clozapine lowers the epileptic threshold, leading to seizures, which are severe side effects of antipsychotics that result in multiple complications. Clozapine-related seizures are generally considered to be dose-dependent and especially rare in the low-dose (150-300 mg/d) clozapine treated population. Due to clinical rarity, little is known about its clinical characteristics and treatment. CASE SUMMARY: A 62-year-old Chinese man with a 40-year history of treatment-resistant schizophrenia presented to the Emergency Department with symptoms of myoclonus, consciousness disturbance and vomiting after taking 125 mg clozapine. Upon admission, the patient had a suddenly generalized tonic-clonic seizure lasting for about half a minute with persistent disturbance of consciousness, fever, cough and bloody sputum, which was considered to be low-dose clozapine-related seizure. After antiepileptic and multiple anti-infection treatments, the patient was discharged without epileptic or psychotic symptoms. CONCLUSION: Our aim is to highlight the early prevention and optimal treatment of clozapine-related seizure through case analysis and literature review.

Comparison of Treatment, Cost, and Survival in Patients With Metastatic Colorectal Cancer in Western Washington, United States, and British Columbia, Canada.

PURPOSE: Few studies have directly compared health care utilization, costs, and outcomes between patients treated in the US multipayer health system and Canada's single-payer system. Using cancer registry and claims data, we assessed treatment types, costs, and survival for patients with metastatic colorectal cancer (mCRC) in Western Washington State (WW) and British Columbia (BC). MATERIALS AND METHODS: Patients age ≥ 18 years diagnosed with mCRC in 2010 and later were identified from the BC Cancer database and a regional database linking WW SEER to claims from Medicare and two large commercial insurers. Demographics, treatment characteristics, costs of systemic therapy, and survival data were obtained from these databases and compared between the two regions. RESULTS: A total of 1,592 patients from BC and 901 from WW were included in the study. Median age was similar (BC, 66 years; WW, 63 years), but patients in BC were more likely to be male (57.1% v 51.2%; P ≤ .01) and to have de novo metastatic disease (61.0% v 38.3%; P ≤ .01). The use of radiation therapy was similar between regions (BC, 31.2%; WW, 33.9%; P = .18), but primary tumor resection was more common in BC (74.1% v 66.3%; P ≤ .01) as was hepatic metastasectomy (12.4% v 2.3%; P ≤ .01). Similar percentages of patients received systemic therapy (BC, 68.8%; WW, 67.1%; P = .40), but costs were significantly higher for first-line systemic therapy in WW ($6,226 v $15,792 per patient per month; P ≤ .01). Median overall survival was similar (BC, 16.9 months; WW, 18 months). CONCLUSION: Cost of systemic therapy for mCRC was significantly higher for patients in WW than in BC, but this did not translate to a difference in overall survival.

Inhibitory Role of TRIP-Br1/XIAP in Necroptosis under Nutrient/Serum Starvation.

Currently, many available anti-cancer therapies are targeting apoptosis. However, many cancer cells have acquired resistance to apoptosis. To overcome this problem, simultaneous induction of other types of programmed cell death in addition to apoptosis of cancer cells might be an attractive strategy. For this purpose, we initially investigated the inhibitory role of TRIP-Br1/XIAP in necroptosis, a regulated form of necrosis, under nutrient/serum starvation. Our data showed that necroptosis was significantly induced in all tested 9 different types of cancer cell lines in response to prolonged serum starvation. Among them, necroptosis was induced at a relatively lower level in MCF-7 breast cancer line that was highly resistant to apoptosis than that in other cancer cell lines. Interestingly, TRIP-Br1 oncogenic protein level was found to be very high in this cell line. Upregulated TRIP-Br1 suppressed necroptosis by repressing reactive oxygen species generation. Such suppression of necroptosis was greatly enhanced by XIAP, a potent inhibitor of apoptosis. Our data also showed that TRIP-Br1 increased XIAP phosphorylation at serine87, an active form of XIAP. Our mitochondrial fractionation data revealed that TRIPBr1 protein level was greatly increased in the mitochondria upon serum starvation. It suppressed the export of CypD, a vital regulator in mitochondria-mediated necroptosis, from mitochondria to cytosol. TRIP-Br1 also suppressed shikoninmediated necroptosis, but not TNF-α-mediated necroptosis, implying possible presence of another signaling pathway in necroptosis. Taken together, our results suggest that TRIPBr1/XIAP can function as onco-proteins by suppressing necroptosis of cancer cells under nutrient/serum starvation.

Low Temperature Thermal Atomic Layer Deposition of Aluminum Nitride Using Hydrazine as the Nitrogen Source.

Aluminum nitride (AlN) thin films were grown using thermal atomic layer deposition in the temperature range of 175-350 °C. The thin films were deposited using trimethyl aluminum (TMA) and hydrazine (N2H4) as a metal precursor and nitrogen source, respectively. Highly reactive N2H4, compared to its conventionally used counterpart, ammonia (NH3), provides a higher growth per cycle (GPC), which is approximately 2.3 times higher at a deposition temperature of 300 °C and, also exhibits a low impurity concentration in as-deposited films. Low temperature AlN films deposited at 225 °C with a capping layer had an Al to N composition ratio of 1:1.1, a close to ideal composition ratio, with a low oxygen content (7.5%) while exhibiting a GPC of 0.16 nm/cycle. We suggest that N2H4 as a replacement for NH3 is a good alternative due to its stringent thermal budget.

The humeral head as a potential donor source for osteochondral allograft transfer to the knee.

This study aimed to determine whether osteochondral allograft plugs from the humeral head are a good topographic match to recipient sites on the femoral condyle. If so, the donor pool for allograft osteochondral transplantation to the knee may increase. Simulated osteochondral grafts of 1-cm, 1.5-cm, and 2-cm diameters were taken from the surface map of the humeral heads and superimposed and optimized on recipient sites of identical size on the femoral condyles. Primary measurement criteria included contour mismatch and circumferential step-off. These measurements increased with donor plug size. For the 1-cm and 1.5-cm plugs, the lowest mean mismatch (0.068 mm and 0.110 mm, respectively) and step-off (0.057 mm and 0.154 mm, respectively) occurred at the 30 degree medial position. For the 2-cm plugs, the lowest mean mismatch (0.183 mm) and step-off (0.227 mm) occurred at the 60 degree lateral position. Although 1-cm osteochondral plugs were a good topographic match to the recipient sites, the 2-cm plugs had a mismatch approaching 0.5 mm, an offset with a demonstrated peak contact pressure > 40% higher than normal. The topographic match of the humeral head suggests it is a potential donor source for osteochondral allograft transfer to the distal femur.

[Six cases with Behcet's disease presenting cervical ulcer].

OBJECTIVE: To investigate the clinical feature and strategy on diagnosis and treatment of cervical ulcer in Behcet's disease. METHODS: From Jan 2000 to Apr 2008, the medical documents of 6 cases with cervical ulcer in Behcet's disease were reviewed retrospectively, who were treated in No.2 hospital affiliated to Wenzhou Medical School RESULTS: (1) General information: all 6 patients with cervical ulcer were diagnosed as Behcet's disease clinically, the mean age of all patients is 33.5 years. (2) CLINICAL FEATURE: the initial symptoms was oral ulcer in 5 cases and erythematic nodosum in 1 case. The typical characteristics of cervical ulcer in Behcet's disease was vaginal purulent discharge. Five among 6 cases presented it. The cervical ulcer in Behcet's disease exhibited the following features: the isolated well-defined ulcers with different size and different deep distributed on the uterine cervix, and the top of ulcer was covered by yellow discharge which was not easy to erase. The duration between the onset symptom and cervical ulcer was calculated to be 2.1 to 7 years. (3) Risk factors for cervical ulcer: operation of drawing intrauterine devices (IUD) in 2 cases, artifical abortion in 2 cases, cervical biopsy in 1 cases, and no factors in the other one case was identified. (4) TREATMENT: The cervical ulcer in Behcet's disease can be treated by the topical application of recombinant bovine basic fibroblast growth factor (rb-bFGF). If ulcer disease existing in other site, systemic corticosteroids management was warranted. (5) Recurrence: 1 case with recurrent disease was observed after 8 months when completing treatment, the other 5 cases did not show recurrence during 3 months-8 years follow-up. CONCLUSIONS: The cervical ulcer in Behcet's disease most commonly occurred after cervical operation. The diagnosis should be derived from comprehensive symptoms analysis. The topical application of rb-bFGF on ulcer site of cervix could get satisfied outcome. When necessary, systemic corticosteroids administration could be considered.

Canal neuromasts enhance foraging in zebrafish (Danio rerio).

Aquatic animals commonly sense flow using superficial neuromasts (SNs), which are receptors that extend from the body's surface. The lateral line of fishes is unique among these systems because it additionally possesses receptors, the canal neuromasts (CNs), that are recessed within a channel. The lateral line has inspired the development of engineered sensors and concepts in the analysis of flow fields for submersible navigation. The biophysics of CNs are known to be different from the SNs and thereby offer a distinct submodality. However, it is generally unclear whether CNs play a distinct role in behavior. We therefore tested whether CNs enhance foraging in the dark by zebrafish (Danio rerio), a behavior that we elicited with a vibrating rod. We found that juvenile fish, which have only SNs, bite at this rod at about one-third the rate and from as little as one-third the distance of adults for a high-frequency stimulus (50 < f  < 100 Hz). We used novel techniques for manipulating the lateral line in adults to find that CNs offered only a modest benefit at a lower frequency (20 Hz) and that foraging was mediated entirely by cranial neuromasts. Consistent with our behavioral results, biophysical models predicted CNs to be more than an order of magnitude more sensitive than SNs at high frequencies. This enhancement helps to overcome the rapid spatial decay in high-frequency components in the flow around the stimulus. These findings contrast what has been previously established for fishes that are at least ten-times the length of zebrafish, which use trunk CNs to localize prey. Therefore, CNs generally enhance foraging, but in a manner that varies with the size of the fish and its prey. These results have the potential to improve our understanding of flow sensing in aquatic animals and engineered systems.

Anticancer activity of gomisin J from Schisandra chinensis fruit.

In attempting to identify effective anticancer drugs from natural products that are harmless to humans, we found that the gomisin J from Schisandra chinensis fruit has anticancer activity. Schisandra chinensis fruits are used in traditional herbal medicine and gomisin J is one of their chemical constituents. In the present study, we examined the anticancer activity of gomisin J in MCF7 and MDA-MB-231 breast cancer cell lines and in MCF10A normal cell line, in a time- and concentration-dependent manner. Our data revealed that gomisin J exerted a much stronger cytotoxic effect on MCF7 and MDA-MB-231 cancer cells than on MCF10A normal cells. Gomisin J suppressed the proliferation and decreased the viability of MCF7 and MDA-MB-231 cells at relatively low (<10 µg/ml) and high (>30 µg/ml) concentrations, respectively. Our data also revealed that gomisin J induced necroptosis, a programmed form of necrosis, as well as apoptosis. Notably, gomisin J predominantly induced necroptosis in MCF7 cells that are known to have high resistance to many pro-apoptotic anticancer drugs, while MDA-MB-231 exhibited a much lower level of necroptosis but instead a higher level of apoptosis. This data indicated the possibility that it may be used as a more effective anticancer drug, especially in apoptosis-resistant malignant cancer cells. In an extended study, gomisin J exhibited a strong cytotoxic effect on all tested various types of 13 cancer cell lines, indicating its potential to be used against a wide range of different types of cancer cells.

Inhibitory role of AMP­activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation.

Simultaneous induction of other types of programmed cell death, alongside apoptosis, in cancer cells may be considered an attractive strategy for the development of more effective anticancer therapies. The present study aimed to investigate the role of AMP­activated protein kinase (AMPK) in nutrient/serum starvation­induced necroptosis, which is a programmed form of necrosis, in the presence or absence of p53. The present study detected higher cell proliferation and lower cell death rates in the HCT116 human colon cancer cell line containing a p53 null mutation (HCT116 p53­/­) compared with in HCT116 cells harboring wild­type p53 (HCT116 p53+/+), as determined using a cell viability assay. Notably, western blot analysis revealed a relatively lower level of necroptosis in HCT116 p53­/­ cells compared with in HCT116 p53+/+ cells. Investigating the mechanism, it was revealed that necroptosis may be induced in HCT116 p53+/+ cells by significantly increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), whereas little alterations were detected in HCT116 p53­/­ cells. Unexpectedly, a much lower level of ATP was detected in HCT116 p53­/­ cells compared with in HCT116 p53+/+ cells. Accordingly, AMPK phosphorylation on the Thr172 residue was markedly increased in HCT116 p53­/­ cells. Furthermore, western blot analysis and ROS measurements indicated that AMPK inhibition, using dorsomorphin dihydrochloride, accelerated necroptosis by increasing ROS generation in HCT116 p53­/­ cells. However, AMPK activation by AICAR did not suppress necroptosis in HCT116 p53+/+ cells. In conclusion, these data strongly suggested that AMPK activation may be enhanced in HCT116 p53­/­ cells under serum­depleted conditions via a drop in cellular ATP levels. In addition, activated AMPK may be at least partially responsible for the inhibition of necroptosis in HCT116 p53­/­ cells, but not in HCT116 p53+/+cells.

[Effects of Long-term Poly-P Deficiency on the Metabolic Properties of Accumulibacter in AO-SBR System].

To investigate the changes in microbial community structure and metabolic properties of Accumulibacter under long-term Poly-P deficiency, an activated sludge enriched with Accumulibacter was inoculated into two SBR reactors, where sodium acetate and sodium propionate were used separately as organic carbon sources. The two reactors were operated for 60 days with an influent PO43--P concentration of 2.5 mg·L-1. The phosphorus removal performance, sludge production, and changes in the microbial community structure of the systems were analyzed. The results indicated that both SBR systems showed good performance of phosphorus and organic matter removal. However, microorganisms in both systems showed glycogen-accumulating metabolism properties under long-term Poly-P deficiency. In the unfavorable environment of long-term Poly-P deficiency, Accumulibacter Ⅰ maintained a high abundance (40%±7%) in the propionate SBR system, indicating that Accumulibacter Ⅰ had higher metabolic activity and its metabolic properties could be independent of Poly-P for survival under Poly-P deficiency for a long period. In comparison, propionate is more conducive to Accumulibacter adaptation to lower phosphorus loads, and Accumulibacter Ⅰ is more competitive than Accumulibacter Ⅱ under lower phosphorus loads.

Olaparib tablets for the treatment of germ line BRCA-mutated metastatic breast cancer.

INTRODUCTION: Germ line BRCA mutations (gBRCAm) are diagnosed in approximately 5% of unselected breast cancer patients. Olaparib is a new treatment option for patients with a gBRCAm who have metastatic HER2-negative breast cancer. Areas covered: Olaparib is an oral poly (ADP-ribose) polymerase inhibitor that has been shown in phase I-III clinical trials to have single-agent efficacy in breast cancer patients with gBRCAm. The recent phase III OlympiAD study demonstrated a statistically significant progression-free survival benefit compared with the chemotherapy control arm, although an overall survival benefit has not been demonstrated. The most common adverse events seen with olaparib include nausea, anemia, and vomiting. The most common grade 3 adverse events are anemia and neutropenia. Expert commentary: The US FDA-approved olaparib tablets in January 2018 for the treatment of patients with a gBRCAm and metastatic HER2-negative breast cancer. This is a well-tolerated and effective treatment option for this patient population, particularly in patients with triple-negative breast cancer in which chemotherapy is the only alternative. More data are needed to understand the role of olaparib in combination with endocrine therapy, other targeted agents, and chemotherapy, as well as sequentially with platinum chemotherapy in the metastatic setting.