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A myriad of inflammatory cytokines regulate signaling pathways to maintain cellular homeostasis. The IκB kinase (IKK) complex is an integration hub for cytokines that govern nuclear factor κB (NF-κB) signaling. In response to inflammation, IKK is activated through recruitment to receptor-associated protein assemblies. How and what information IKK complexes transmit about the milieu are open questions. Here, we track dynamics of IKK complexes and nuclear NF-κB to identify upstream signaling features that determine same-cell responses. Experiments and modeling of single complexes reveal their size, number, and timing relays cytokine-specific control over shared signaling mechanisms with feedback regulation that is independent of transcription. Our results provide evidence for variable-gain stochastic pooling, a noise-reducing motif that enables cytokine-specific regulation and parsimonious information transfer. We propose that emergent properties of stochastic pooling are general principles of receptor signaling that have evolved for constructive information transmission in noisy molecular environments., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Cellular microenvironments are dynamic. When exposed to extracellular cues, such as changing concentrations of inflammatory cytokines, cells activate signaling networks that mediate fate decisions. Exploring responses broadly to time-varying microenvironments is essential to understand the information transmission capabilities of signaling networks and how dynamic milieus influence cell fate decisions. Here, we present a gravity-driven cell culture and demonstrate that the system accurately produces user-defined concentration profiles for one or more dynamic stimuli. As proof of principle, we monitor nuclear factor-κB activation in single cells exposed to dynamic cytokine stimulation and reveal context-dependent sensitivity and uncharacterized single-cell response classes distinct from persistent stimulation. Using computational modeling, we find that cell-to-cell variability in feedback rates within the signaling network contributes to different response classes. Models are validated using inhibitors to predictably modulate response classes in live cells exposed to dynamic stimuli. These hidden capabilities, uncovered through dynamic stimulation, provide opportunities to discover and manipulate signaling mechanisms., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Target-centric drug development strategies prioritize single-target potency in vitro and do not account for connectivity and multi-target effects within a signal transduction network. Here, we present a systems biology approach that combines transcriptomic and structural analyses with live-cell imaging to predict small molecule inhibitors of TNF-induced NF-κB signaling and elucidate the network response. We identify two first-in-class small molecules that inhibit the NF-κB signaling pathway by preventing the maturation of a rate-limiting multiprotein complex necessary for IKK activation. Our findings suggest that a network-centric drug discovery approach is a promising strategy to evaluate the impact of pharmacologic intervention in signaling.

Although cytokine-dependent dynamics of nuclear factor κB (NF-κB) are known to encode information that regulates cell fate decisions, it is unclear whether single-cell responses are switch-like or encode more information about cytokine dose. Here, we measure the dynamic subcellular localization of NF-κB in response to a range of tumor necrosis factor (TNF) stimulation conditions to determine the prevailing mechanism of single-cell dose discrimination. Using an information theory formalism that accounts for signaling dynamics and non-responsive cell subpopulations, we find that the information transmission capacity of single cells exceeds that predicted from a switch-like response. Instead, we observe that NF-κB dynamics within single cells contain sufficient information to encode multiple, TNF-dependent cellular states, and have an activation threshold that varies across the population. By comparing single-cell responses to an internal, experimentally observed reference, we demonstrate that cells can grade responses to TNF across several orders of magnitude in concentration. This suggests that cells contain additional control points to fine-tune their cytokine responses beyond the decision to activate., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatosplenic T-cell lymphoma (HSTCL) is a rare non-Hodgkin lymphoma with a high mortality rate. Higher incidence is reported in patients with inflammatory bowel disease, specifically in male patients that are younger than 35 years, and have been treated with thiopurine and tumor necrosis factor (TNF)-α inhibitor combination therapy for over 2 years. In this case report we describe a 47-year-old patient with Crohn's disease (CD) who developed HSTCL after having been treated with thiopurine monotherapy for 14 years. To our best knowledge, only eleven cases exist of patients with CD who developed HSTCL while on thiopurine monotherapy. We report the first patient with CD, older than 35 years, who developed HSTCL while on thiopurine monotherapy. This emphasizes that HSTCL risk is not limited to young men receiving both thiopurines and TNF-α inhibitors., Competing Interests: Conflict-of-interest statement: All the authors have no conflicts of interests to declare.

Scientific evidence concerning the treatment of acute diverticulitis is scarce. We describe 2 patients with this condition in this article. The first, a 64-year-old man, came to the emergency room because he had experienced persistent abdominal pain for the previous 4 days. He was diagnosed with uncomplicated diverticulitis. The second patient, a 58-year-old woman, had had pain in her left lower abdomen for 4 weeks; the pain appeared to have been caused by complicated diverticulitis. Both patients were treated conservatively. Only the patient with complicated diverticulitis was administered antibiotics; she underwent surgery at a later date because of persistent pain. Several guidelines recommend the administration of antibiotics; however, a number of recent studies have revealed no benefit to the clinical course from the use of antibiotics. The Dutch guideline, therefore, recommends withholding antibiotics in the acute phase. Conclusive evidence on the best treatment for patients with frequent recurrences or chronic symptoms after an episode of acute diverticulitis is not available. Guidelines advise a personalised treatment strategy for each patient. More research is necessary on the effect of mesalazine in these cases.

Three male patients aged between 50 and 70 years were referred with jaundice and weight loss. Imaging showed a pancreatic mass and changes in the calibre of the choledochal or pancreatic duct, suggestive of malignancy. Two patients were operated on. One patient was considered to have an unresectable carcinoma but showed remarkable clinical improvement after steroids were given for his poor condition. In the other patient a resection was performed. Histology showed IgG4-positive plasma cell infiltration without signs of malignancy. Eventually these patients were diagnosed with auto-immune pancreatitis (AIP). In the third patient AIP was considered beforehand and this patient was treated with steroids. He responded quickly both clinically and radiologically. CT imaging showed complete remission of the mass. AIP is a benign inflammatory process which can mimic pancreatic carcinoma. In doubtful cases, a short trial of steroids might be considered.

Background: Resistance to chemotherapeutic agents is a major problem in the treatment of patients with gastric cancer. Many factors may play a role in the resistance to cytotoxic drugs. The purpose of this study was to investigate the significance of glutathione (GSH), glutathione S-transferases (GSTs) and cell proliferation as parameters for response and resistance to chemotherapy in patients with gastric cancer., Methods: In endoscopic biopsies of normal and malignant gastric tissue from 15 patients with gastric cancer treated by chemotherapy, the GSH content, GST activity and levels of GST Alpha, Mu and Pi isoenzymes were determined before the start of chemotherapy and after 2 and 6 cycles. Furthermore, cell proliferation was determined in these biopsies after in vivo Iododeoxyuridine (IdU) labelling., Results: None of the above mentioned parameters were predictive for response to chemotherapy. After 2 courses of chemotherapy there was an increase of median GSH content (367%) in three patients with partial response (PR), whereas there was a decrease (43%) in five patients with progressive disease (PD) (p < 0.05). Median GST activity increased (257%) in patients with PR and declined (31%) in patients with PD (p < 0.05). GST Pi showed a median increase of 326% in responding patients and a 59% decrease in progressive patients (p < 0.05). There were no significant changes in GST Alpha and Mu. In seven patients with stable disease (SD) there were no significant changes in GSH/GST parameters., Conclusion: GSH/GST parameters and IdU labelling index determined before the start of chemotherapy were not predictive for response to that chemotherapy. However, the differences of GSH and GST parameters between responding and progressive patients suggests a role for the GSH/GST system in the susceptibility of gastric tumor cells to chemotherapy.

Background: In vivo labelling with synthetic thymidine analogues, such as Iododeoxyuridine (IdU) and Bromodeoxyuridine (BrdU), has frequently been used to estimate tumour proliferation. However, this method requires intravenous administration of IdU or BrdU, thymidine analogues that are potential mutagens. Recently, the monoclonal antibody MIB-1 has been developed, recognizing the Ki-67 nuclear antigen, which is associated with cell cycle proliferation and is found throughout the cell cycle (G1, S, G2 and M phases), but not in resting (G0) cells. We studied the correlation between the MIB-1 labelling index (LI) and the IdU labelling index in normal and malignant gastric tissue., Patients and Methods: Twenty patients with gastric cancer received an intravenous injection of IdU (200 mg/m2) before surgery. Specimens were obtained from gastric carcinoma and adjacent normal gastric tissue. The samples were fixed in formalin and immunohistochemical analyses of IdU LI and MIB-1 LI were performed. The LI was defined as the percentage of labelled nuclei of 5000 nuclei counted., Results: The IdU LI ranged from 3.3% to 18.2% in gastric carcinoma and from 0.5% to 5.6% in adjacent normal gastric mucosa, whereas the MIB-1 LI ranged from 4.2% to 46.0% in gastric cancer and from 1.3% to 25.1% in adjacent normal gastric mucosa. Comparison of IdU LI with MIB-1 LI, using the Spearman rank correlation coefficient test showed a significant correlation between IdU LI and MIB-1 LI in normal gastric tissue (r = 0.63, p < 0.05). However, in gastric carcinoma no significant correlation was found between either proliferation marker (r = 0.07, N.S.)., Conclusion: MIB-1 accurately reflects the in vivo IdU LI in normal gastric tissue, whilst in gastric carcinoma the MIB-1 LI does not seem to be a substitute for the in vivo IdU LI.

Cell kinetic data may be important indicators of clinical behaviour in many types of cancer. Recently, several antibodies to cell-cycle associated antigens have been characterised. This overview summarises the advantages and disadvantages of different methods for the assessment of cell proliferation. Moreover, the prognostic value of proliferative activity in gastric cancer is discussed and suggestions for future research are given.

Glutathione S-transferases (GSTs) are a family of isoenzymes that play an important role in protecting cells against cytotoxic and carcinogenic agents. The distribution and levels of GST Alpha and Pi in normal and malignant gastric tissue of 34 patients with gastric cancer were examined immunohistochemically. Expression of GST Alpha and Pi was observed in 47 and 100 percent of the tumors, respectively. In normal mucosa both enzyme classes were present in 100 percent of the specimens. Mucous cells showed staining for GST Alpha and Pi in 88 and 97 percent, parietal cells in 93 and 67 percent, and chief cells in 82 and 30 percent, respectively. No correlation was observed between the amount or pattern of GST Alpha or Pi in carcinomas and the clinical and pathological characteristics of the patients. So it can be concluded that both GST Alpha and Pi cannot be considered as prognostic factors for gastric cancer.

Patients with gastric adenocarcinomas have a poor prognosis. Because curative surgery is often impossible (metastatic disease) or extremely difficult (locally advanced tumors), and the majority of patients undergoing curative resection relapse, chemotherapy has been actively studied in gastric cancer. Many drugs have shown activity; however, single-agent chemotherapy failed to demonstrate increased survival benefit. Several combination regimens have been developed with high activity in locally advanced and metastatic disease. Among them are 5-fluorouracil (5-FU) plus high dose methotrexate plus doxorubicin (FAMTX), etoposide plus doxorubicin plus cisplatin (EAP), etoposide plus leucovorin plus 5-FU (ELF), and epirubicin plus cisplatin plus 5-FU (ECF). Although the response rates of these schedules are encouraging, the toxicity is considerable. Randomized trials comparing chemotherapy with best supportive care showed an increase in overall survival and in quality-of-life. Up to now adjuvant chemotherapy in curatively resected gastric cancer patients has failed to improve survival as compared with surgical controls. Phase II trials with preoperative chemotherapy have shown very promising results, but results of randomized trials should be awaited to judge the real value of this approach. At this moment it cannot yet be estimated whether preoperative chemotherapy does positively influence the resection rate and survival of patients with clinically resectable tumors.

Acute renal failure is a frequent complication at the Intensive Care Department. For this complication dialysis is often necessary. In our Intensive Care Department we have opted for continuous arteriovenous hemodiafiltration (CAVHD) as the treatment of first choice for patients with acute renal failure. We describe the results in 18 patients treated with CAVHD. In all patients an arterious and a venous catheter were placed, in most cases in the femoral artery and vein. A capillary hemofilter was placed between the catheters. In the filter a counterflow mechanism took place. All patients were successfully treated with CAVHD. Haemodynamic instability as an effect of the treatment did not appear. The fluid and electrolyte balance was perfectly under control. Renal function was recovered in 7 patients. Twelve patients died. The cause of death was never associated with the renal failure or with the CAVHD treatment.

Information about chemotherapy side effects and the efficacy of self-care activities used to deal with these side effects is needed to direct nursing interventions for patients receiving chemotherapy. Using the self-care diary (SCD) developed for this study, a sample of 49 adult patients with cancer recorded their side effects, rated the severity of each side effect, and reported on the use and efficacy of self-care activities two days after treatment. Data were collected again five days after treatment to examine the test-retest reliability of the side effect severity component of the SCD. The most common side effect, experienced by 81% of the subjects, was fatigue. Other side effects reported by more than one-third of the subjects were sleeping difficulty, nausea, decreased appetite, and changes in taste or smell. The most frequently reported side effects received mean severity scores indicative of moderate severity. The most commonly used self-care activities were rated as providing some relief to moderate relief of individual side effects. None of the reported self-care activities received mean efficacy ratings that indicated complete side effect relief.

Ten double-blind randomized studies with omeprazole versus ranitidine in duodenal ulcer healing have been published. The total number of patients in the trials amounted to 2225. To detect treatment differences, a meta-analysis was performed. After 2 and 4 weeks of treatment results have been evaluated. After 2 weeks of treatment omeprazole produced higher healing rates than ranitidine in nine studies. However, at 4 weeks numerical differences in favour of omeprazole were found in nine studies. Relief of ulcer symptoms occurred more rapidly with omeprazole than ranitidine. No major clinical or biochemical side effects were recorded. However, no data are available about maintenance therapy in double-blind randomized studies comparing both drugs or about rebleeding rates in bleeding duodenal ulcer treatment.

A phase I study with continuous administration of epirubicin for 21 days using a venous access port and a portable pump was performed. The first dose step was 2 mg/m2/d for 21 days. Interval between courses was 3 weeks. Dose increment per step was 1 mg/m2/d. Twenty-two patients entered the study and received a total of 58 courses with a median of two (range, one to nine). Up to 5 mg/m2/d no toxicity (according to World Health Organization [WHO] criteria) occurred. At 6 mg/m2/d (six pts), one patient had leukopenia grade 3. Two others had some hair loss. At 7 mg/m2/d (four patients), all patients developed mucositis (two grade 3). Three patients had bone marrow depression (one grade 3 anemia, one grade 4 leukocytopenia), and one patient developed the hand-foot syndrome. No other toxicity occurred in the patients. One patient obtained a partial response (18 weeks), ten had stable disease (12 to 54 weeks), seven had progressive disease, and four were not evaluable for response. One patient developed cellulitis around the port, responding to antibiotic treatment; one patient developed a vena cava superior syndrome that resolved with urokinase and removal of the access port. No septicemia occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with fluorometric detection. Plasma steady state was reached after 57 hours. During steady state there was a linear relationship between epirubicin dose administered and epirubicin level in plasma (r = .58, P less than .05), whole blood (r = .75, P less than .005), and in leukocytes (r = .68, P less than .05). The area under the curve in leukocytes was higher with continuous infusion of 6 mg/m2 for 21 days compared with bolus injection of 80 mg/m2. This method of continuous infusion with epirubicin may be a way to increase intracellular drug-uptake as expressed by intracellular area under curve (AUC). We recommend 6 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.

Vindesine 1.75 mg/m2, twice weekly for 2 weeks followed by 2 weeks rest, was given to 26 lung cancer patients. In 6 patients a partial response was seen (23%). Neurotoxicity was present in 15 patients after 1 course; in 6 patients this was the reason for stopping therapy. This regimen has no advantage over weekly vindesine.