Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling.

Hepatocellular carcinoma (HCC) is a slowly developing malignancy postulated to evolve from premalignant lesions in chronically damaged livers. However, it was never established that premalignant lesions actually contain tumor progenitors that give rise to cancer. Here, we describe isolation and characterization of HCC progenitor cells (HcPCs) from different mouse HCC models. Unlike fully malignant HCC, HcPCs give rise to cancer only when introduced into a liver undergoing chronic damage and compensatory proliferation. Although HcPCs exhibit a similar transcriptomic profile to bipotential hepatobiliary progenitors, the latter do not give rise to tumors. Cells resembling HcPCs reside within dysplastic lesions that appear several months before HCC nodules. Unlike early hepatocarcinogenesis, which depends on paracrine IL-6 production by inflammatory cells, due to upregulation of LIN28 expression, HcPCs had acquired autocrine IL-6 signaling that stimulates their in vivo growth and malignant progression. This may be a general mechanism that drives other IL-6-producing malignancies.

2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, ß-adrenergic receptor antagonists (also known as ß-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.

Methionine restriction of glioma does not induce MGMT and greatly improves temozolomide efficacy in an orthotopic nude-mouse model: A potential curable approach to a clinically-incurable disease.

Glioma is a highly recalcitrant disease with a 5-year survival of 6.8 %. Temozolomide (TMZ), first-line therapy for glioma, is more effective in O6-methylguanine-DNA methyltransferase (MGMT)-negative gliomas than in MGMT-positive gliomas as MGMT confers resistance to TMZ. Methionine restriction is effective for many cancers in mouse models including glioma. The concern is that methionine restriction could induce MGMT by decreasing DNA methylation and confer resistance to TMZ. In the present study, we investigated the efficacy of combining methionine restriction with TMZ for the treatment of MGMT-negative glioma, and whether methionine restriction induced MGMT. Human MGMT-negative U87 glioma cells were used to determine the efficacy of TMZ combined with methionine restriction. Recombinant methioninase (rMETase) inhibited U87 glioma growth without induction of MGMT in vitro. The combination of rMETase and TMZ inhibited U87 cell proliferation more than either agent alone in vitro. In the orthotopic nude-mouse model, the combination of TMZ and a methionine-deficient diet was much more effective than TMZ alone: two mice out of five were cured of glioma by the combination. No mice died during the treatment period. Methionine restriction enhanced the efficacy of TMZ in MGMT-negative glioma without inducing MGMT, demonstrating potential clinical promise for improved outcome of a currently incurable disease.

Targeting Patient-Derived Orthotopic Gastric Cancers with a Fluorescent Humanized Anti-CEA Antibody.

BACKGROUND: Gastric cancer poses a major diagnostic and therapeutic challenge as surgical resection provides the only opportunity for a cure. Specific labeling of gastric cancer could distinguish resectable and nonresectable disease and facilitate an R0 resection, which could improve survival. METHODS: Two patient-derived gastric cancer lines, KG8 and KG10, were established from surgical specimens of two patients who underwent gastrectomy for gastric adenocarcinoma. Harvested tumor fragments were implanted into the greater curvature of the stomach to establish patient-derived orthotopic xenograft (PDOX) models. M5A (humanized anti-CEA antibody) or IgG control antibodies were conjugated with the near-infrared dye IRDye800CW. Mice received 50 µg of M5A-IR800 or 50 µg of IgG-IR800 intravenously and were imaged after 72 hr. Fluorescence imaging was performed by using the LI-COR Pearl Imaging System. A tumor-to-background ratio (TBR) was calculated by dividing the mean fluorescence intensity of the tumor versus adjacent stomach tissue. RESULTS: M5A-IR800 administration resulted in bright labeling of both KG8 and K10 tumors. In the KG8 PDOX models, the TBR for M5A-IR800 was 5.85 (SE ± 1.64) compared with IgG-IR800 at 0.70 (SE ± 0.17). The K10 PDOX models had a TBR of 3.71 (SE ± 0.73) for M5A-IR800 compared with 0.66 (SE ± 0.12) for IgG-IR800. CONCLUSIONS: Humanized anti-CEA (M5A) antibodies conjugated to fluorescent dyes provide bright and specific labeling of gastric cancer PDOX models. This tumor-specific fluorescent antibody is a promising potential clinical tool to detect the extent of disease for the determination of resectability as well as to visualize tumor margins during gastric cancer resection.

Hematologic and biochemical inflammatory markers increase with body mass and positively correlate in adolescents.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease that has its origins in childhood. The goal of this study was to explore the relationships of hematologic inflammatory markers to body mass, biochemical inflammatory markers and cardiometabolic risk factors. METHODS: Healthy, white, non-Hispanic identifying adolescents (n = 75, age 12 to 18 years) were enrolled. Measures studied included body mass index percentile (BMI%), neutrophil and platelet to lymphocyte ratio (NLR, PLR), pan immune inflammation value (PIV), lipids, augmentation index, reactive hyperemia, inflammatory markers (interleukin 6: IL6, c-reactive protein: CRP), complement (C3, C3a, C4, C4a, C5a) insulin secretion and insulin sensitivity (oral glucose tolerance test: Matusda index, and disposition index (DI)). RESULTS: NLR (rS = 0.31, p < 0.01), PLR (rS = 0.32, p < 0.01), PIV (rS = 0.32, p < 0.01) and CRP (rS = 0.51, p < 0.001) all positively correlated with BMI% but IL-6 did not. NLR, PLR and PIV all positively correlated with each other. NLR correlated with the reactive hyperemia response (rS = 0.29, p < 0.02) but this relationship was lost when BMI% was included. NLR positively correlated with C3a, C4, CRP and IL6 even when BMI% was included. CONCLUSION: In healthy adolescents hematologic markers of inflammation increase with increasing body mass and neutrocyte to lymphocyte ratio is associated with increased complement and inflammatory markers independent of obesity. IMPACT STATEMENT: Hematologic and biochemical markers of inflammation increase with increased body mass in healthy adolescents. Hematologic and biochemical markers of inflammation are positively related independent of body mass in healthy adolescents. Hematologic inflammatory markers are not related to markers of cardiometabolic risk in healthy adolescents.

Humanized Anti-Carcinoembryonic Antigen Antibodies Brightly Target and Label Gastric Cancer in Orthotopic Mouse Models.

INTRODUCTION: Gastric cancer poses a major therapeutic challenge. Improved visualization of tumor margins at the time of gastrectomy with fluorescent tumor-specific antibodies could improve outcomes. The present report demonstrates the potential of targeting gastric cancer with a humanized anti-carcinoembryonic antigen (CEA) antibody in orthotopic mouse models. METHODS: MKN45 cells were injected subcutaneously into nude mice to establish xenograft models. Tumor fragments collected from subcutaneous models were then implanted into the greater curvature of the stomach to establish orthotopic models. For tumor labeling, a humanized anti-CEA antibody (M5A) and IgG as a control, were conjugated with the near-infrared dye IRDye800CW. Time (24-72 h) and dose (50-100 µg) response curves were performed in subcutaneous models. Orthotopic models received 50 µg of M5A-IR800 or 50 µg IgG-IR800 as a control and were imaged after 72 h. Fluorescence imaging was performed on the mice using the LI-COR Pearl Imaging System. RESULTS: In subcutaneous models, tumor to background ratios (TBRs) reached 8.85 at 72 h. Median TBRs of orthotopic model primary tumors were 6.25 (interquartile range [IQR] 6.03-7.12) for M5A-IR800 compared to 0.42 (IQR 0.38-0.54) for control. Abdominal wall metastasis median TBRs were 13.52 (IQR 12.79-13.76) for M5A-IR800 and 3.19 (IQR 2.65-3.73) for the control. Immunohistochemistry confirmed CEA expression within tumors. CONCLUSIONS: Humanized anti-CEA antibodies conjugated to near-infrared dyes provide specific labeling of gastric cancers in mouse models. Orthotopic models demonstrated bright and specific labeling with TBRs greater than ten times that of control. This tumor-specific fluorescent antibody is a promising potential clinical tool for improving visualization of gastric cancer margins at time of surgical resection.

Group A Streptococcus Carriage in Adults in Southern Israel: A Prospective Study.

BACKGROUND: The prevalence of Group A streptococcus (GAS) carriage among adults is studied less than in children. The variability of reported carriage rates is considerably large and differs among diverse geographic areas and populations. OBJECTIVES: To evaluate the prevalence of GAS carriage among adults in Israel. METHODS: In this prospective study, conducted in a large healthcare maintenance organization in Israel, we obtained pharyngeal cultures from adults attending the clinic without upper respiratory tract complaints or fever. Patient data included sex, age, number of children, and religious sectors. RESULTS: From May to December 2022, eight family physicians collected a total of 172 throat swabs (86% response rate). The median age was 37 years (range 18-65); 72.7% were females, 22.7% were ultra-Orthodox Jewish, and 69.2% had children. The prevalence of GAS carriage was 6.98%, 95% confidence interval (95%CI) 3.7%-11.9%. GAS carriers were younger (31.7 vs. 39.3 years, P = 0.046), and the majority were ultra-Orthodox Jews (58.3% vs. 20%, P = 0.006). All GAS carriers were from lower socioeconomic status. When assessing risk factors for GAS carriage using multivariate analysis, only being an ultra-Orthodox Jew was positively related to GAS carriage (adjusted odds ratio 5.6, 95%CI 1.67-18.8). CONCLUSIONS: Being an ultra-Orthodox Jew was the single variable associated with a GAS carriage, which may be related to having many children at home and living in overcrowded areas. Primary care physicians in Israel should recognize this situation when examining patients with sore throats, mainly ultra-Orthodox Jews.

Specific Targeting and Labeling of Colonic Polyps in CPC-APC Mice with Mucin 5AC Fluorescent Antibodies: A Model for Detection of Early Colon Cancer.

Poor visualization of polyps can limit colorectal cancer screening. Fluorescent antibodies to mucin5AC (MUC5AC), a glycoprotein upregulated in adenomas and colorectal cancer, could improve screening colonoscopy polyp detection rate. Adenomatous polyposis coli flox mice with a Cdx2-Cre transgene (CPC-APC) develop colonic polyps that contain both dysplastic and malignant tissue. Mice received MUC5AC-IR800 or IRdye800 as a control IV and were sacrificed after 48 h for near-infrared imaging of their colons. A polyp-to-background ratio (PBR) was calculated for each polyp by dividing the mean fluorescence intensity of the polyp by the mean fluorescence intensity of the background tissue. The mean 25 µg PBR was 1.70 (±0.56); the mean 50 µg PBR was 2.64 (±0.97); the mean 100 µg PBR was 3.32 (±1.33); and the mean 150 µg PBR was 3.38 (±0.87). The mean PBR of the dye-only control was 2.22 (±1.02), significantly less than the 150 µg arm (p-value 0.008). The present study demonstrates the ability of fluorescent anti-MUC5AC antibodies to specifically target and label colonic polyps containing high-grade dysplasia and intramucosal adenocarcinoma in CPC-APC mice. This technology can potentially improve the detection rate and decrease the miss rate of advanced colonic neoplasia and early cancer at colonoscopy.

Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer.

Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic.

The complement system and human autoimmune diseases.

Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis.

Proof of Principle of Combining Fluorescence-Guided Surgery with Photoimmunotherapy to Improve the Outcome of Pancreatic Cancer Therapy in an Orthotopic Mouse Model.

BACKGROUND: Pancreatic cancer is a recalcitrant disease in which R0 resection is often not achieved owing to difficulty in visualization of the tumor margins and proximity of adjacent vessels. To improve outcomes, we have developed fluorescence-guided surgery (FGS) and photoimmunotherapy (PIT) using a fluorescent tumor-specific antibody. METHODS: Nude mice received surgical orthotopic implantation (SOI) of the human pancreatic cancer cell line BxPC-3 expressing green fluorescent protein. An anti-carcinoembryonic antigen-related cell adhesion molecule (CEACAM) monoclonal antibody (6G5j) was conjugated to the 700-nm fluorescent dye IR700DyeDX (6G5j-IR700DX). Three weeks after SOI, 16 mice received 50 µg 6G5j-IR700DX via the tail vein 24 h before surgery and were randomized to two groups: FGS-only (n = 8) and FGS + PIT (n = 8). All tumors were imaged with the Pearl Trilogy imaging system and resected under the guidance of the FLARE imaging system. The FGS + PIT group received PIT of the post-surgical bed at an intensity of 150 mW/cm2 for 30 min. Mice were sacrificed 4 weeks after initial surgery, and tumors were imaged with a Dino-Lite digital microscope, excised, and weighed. RESULTS: The 6G5j-IR700DX dye illuminated the orthotopic pancreatic tumors for FGS and PIT. The metastatic recurrence rate was 100.0% for FGS-only and 25.0% for FGS + PIT (p = 0.007). The average total recurrent tumor weight was 2370.3 ± 1907.8 mg for FGS-only and 705.5 ± 1200.0 mg for FGS + PIT (p = 0.039). CONCLUSIONS: FGS and adjuvant PIT can be combined by using a single antibody-fluorophore conjugate to significantly reduce the frequency of pancreatic cancer recurrence.

PEGylated Fluorescent Anti-carcinoembryonic Antigen Antibody Labels Colorectal Cancer Tumors in Orthotopic Mouse Models.

INTRODUCTION: Colorectal cancer (CRC) patients often develop liver metastasis. However, curative resection of liver metastasis is not always possible due to poor visualization of tumor margins. The present study reports the characterization of a humanized anti-carcinoembryonic antigen monoclonal antibody conjugated to a PEGylated near-infrared dye, that targets and brightly labels human CRC tumors in metastatic orthotopic mouse models. METHODS: The hT84.66-M5A (M5A) monoclonal antibody was conjugated with a polyethylene glycol (PEG) chain that incorporated a near infrared (NIR) IR800 dye to establish M5A-IR800 Sidewinder (M5A-IR800-SW). Nude mice with CRC orthotopic primary tumors and liver metastasis both developed from a human CRC cell line, were injected with M5A-IR800-SW and imaged with the Pearl Trilogy Imaging System. RESULTS: M5A-IR800-SW targeted and brightly labeled CRC tumors, both in primary-tumor and liver-metastasis models. M5A-IR800-SW at 75 µg exhibited highly-specific tumor labeling in a primary-tumor orthotopic model with a median tumor-to-background ratio of 9.77 and in a liver-metastasis orthotopic model with a median tumor-to-background ratio of 7.23 at 96 h. The precise labeling of the liver metastasis was due to lack of hepatic accumulation of M5A-IR800-SW in the liver. CONCLUSIONS: M5A-IR800-SW provided bright and targeted NIR images of human CRC in orthotopic primary-tumor and liver-metastasis mouse models. The results of the present study suggest the clinical potential of M5A-IR800-SW for fluorescence-guided surgery including metastasectomies for CRC. The lack of hepatic NIR signal is of critical importance to allow for precise labeling of liver tumors.

Extracorporeal treatment for ethylene glycol poisoning: systematic review and recommendations from the EXTRIP workgroup.

Ethylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically, treatment of EG toxicity included supportive care, correction of acid-base disturbances and antidotes (ethanol or fomepizole), and extracorporeal treatments (ECTRs), such as hemodialysis. With the wider availability of fomepizole, the indications for ECTRs in EG poisoning are debated. We conducted systematic reviews of the literature following published EXTRIP methods to determine the utility of ECTRs in the management of EG toxicity. The quality of the evidence and the strength of recommendations, either strong ("we recommend") or weak/conditional ("we suggest"), were graded according to the GRADE approach. A total of 226 articles met inclusion criteria. EG was assessed as dialyzable by intermittent hemodialysis (level of evidence = B) as was glycolate (Level of evidence = C). Clinical data were available for analysis on 446 patients, in whom overall mortality was 18.7%. In the subgroup of patients with a glycolate concentration ≤ 12 mmol/L (or anion gap ≤ 28 mmol/L), mortality was 3.6%; in this subgroup, outcomes in patients receiving ECTR were not better than in those who did not receive ECTR. The EXTRIP workgroup made the following recommendations for the use of ECTR in addition to supportive care over supportive care alone in the management of EG poisoning (very low quality of evidence for all recommendations): i) Suggest ECTR if fomepizole is used and EG concentration > 50 mmol/L OR osmol gap > 50; or ii) Recommend ECTR if ethanol is used and EG concentration > 50 mmol/L OR osmol gap > 50; or iii) Recommend ECTR if glycolate concentration is > 12 mmol/L or anion gap > 27 mmol/L; or iv) Suggest ECTR if glycolate concentration 8-12 mmol/L or anion gap 23-27 mmol/L; or v) Recommend ECTR if there are severe clinical features (coma, seizures, or AKI). In most settings, the workgroup recommends using intermittent hemodialysis over other ECTRs. If intermittent hemodialysis is not available, CKRT is recommended over other types of ECTR. Cessation of ECTR is recommended once the anion gap is < 18 mmol/L or suggested if EG concentration is < 4 mmol/L. The dosage of antidotes (fomepizole or ethanol) needs to be adjusted during ECTR.

Targeting Methionine Addiction of Cancer Cells with Methioninase.

All types of cancer cells are addicted to methionine, which is known as the Hoffman effect. Restricting methionine inhibits the growth and proliferation of all tested types of cancer cells, leaving normal cells unaffected. Targeting methionine addiction with methioninase (METase), either alone or in combination with common cancer chemotherapy drugs, has been shown as an effective and safe therapy in various types of cancer cells and animal cancer models. About six years ago, recombinant METase (rMETase) was found to be able to be taken orally as a supplement, resulting in anecdotal positive results in patients with advanced cancer. Currently, there are 8 published clinical studies on METase, including two from the 1990s and six more recent ones. This review focuses on the results of clinical studies on METase-mediated methionine restriction, in particular, on the dosage of oral rMETase taken alone as a supplement or in combination with common chemotherapeutic agents in patients with advanced cancer.

Primary care practitioners' priorities for improving the timeliness of cancer diagnosis in primary care: a European cluster-based analysis.

BACKGROUND: Diagnosing cancer at an early stage increases the likelihood of survival, and more advanced cancers are more difficult to treat successfully. Primary care practitioners (PCPs) play a key role in timely diagnosis of cancer. PCPs' knowledge of their own patient populations and health systems could help improve the planning of more effective approaches to earlier cancer recognition and referral. How PCPs act when faced with patients who may have cancer is likely to depend on how their health systems are organised, and this may be one explanation for the wide variation on cancer survival rates across Europe. OBJECTIVES: To identify and characterise clusters of countries whose PCPs perceive the same factors as being important in improving the timeliness of cancer diagnosis. METHODS: A cluster analysis of qualitative data from an online survey was carried out. PCPs answered an open-ended survey question on how the speed of diagnosis of cancer in primary care could be improved. Following coding and thematic analysis, we identified the number of times per country that an item in a theme was mentioned. k-means clustering identified clusters of countries whose PCPs perceived the same themes as most important. Post-hoc testing explored differences between these clusters. SETTING: Twenty-five primary care centres in 20 European countries. Each centre was asked to recruit at least 50 participants. PARTICIPANTS: Primary care practitioners of each country. RESULTS: In all, 1,351 PCPs gave free-text answers. We identified eighteen themes organising the content of the responses. Based on the frequency of the themes, k-means clustering identified three groups of countries. There were significant differences between clusters regarding the importance of: access to tests (p = 0.010); access to specialists (p = 0.014), screening (p < 0.001); and finances, quotas & limits (p < 0.001). CONCLUSIONS: Our study identified three distinct clusters of European countries within which PCPs had similar views on the factors that would improve the timeliness of cancer diagnosis. Further work is needed to understand what it is about the clusters that have produced these patterns, allowing healthcare systems to share best practice and to reduce disparities.

Trust and trustworthy artificial intelligence: A research agenda for AI in the environmental sciences.

Demands to manage the risks of artificial intelligence (AI) are growing. These demands and the government standards arising from them both call for trustworthy AI. In response, we adopt a convergent approach to review, evaluate, and synthesize research on the trust and trustworthiness of AI in the environmental sciences and propose a research agenda. Evidential and conceptual histories of research on trust and trustworthiness reveal persisting ambiguities and measurement shortcomings related to inconsistent attention to the contextual and social dependencies and dynamics of trust. Potentially underappreciated in the development of trustworthy AI for environmental sciences is the importance of engaging AI users and other stakeholders, which human-AI teaming perspectives on AI development similarly underscore. Co-development strategies may also help reconcile efforts to develop performance-based trustworthiness standards with dynamic and contextual notions of trust. We illustrate the importance of these themes with applied examples and show how insights from research on trust and the communication of risk and uncertainty can help advance the understanding of trust and trustworthiness of AI in the environmental sciences.

Superiority of [11C]methionine over [18F]deoxyglucose for PET Imaging of Multiple Cancer Types Due to the Methionine Addiction of Cancer.

Positron emission tomography (PET) is widely used to detect cancers. The usual isotope for PET imaging of cancer is [18F]deoxyglucose. The premise of using [18F]deoxyglucose is that cancers are addicted to glucose (The Warburg effect). However, cancers are more severely addicted to methionine (The Hoffman effect). [11C]methionine PET (MET-PET) has been effectively used for the detection of glioblastoma and other cancers in the brain, and in comparison, MET-PET has been shown to be more sensitive and accurate than [18F]deoxyglucose PET (FDG-PET). However, MET-PET has been limited to cancers in the brain. The present report describes the first applications of MET-PET to cancers of multiple organs, including rectal, bladder, lung, and kidney. The results in each case show that MET-PET is superior to FDG-PET due to the methionine addiction of cancer and suggest that the broad application of MET-PET should be undertaken for cancer detection.

TRAF6 regulates the signaling pathway influencing colorectal cancer function through ubiquitination mechanisms.

Tumor necrosis factor receptor-associated factor-6 (TRAF6) is a ubiquitin E3 ligase. TRAF6 plays an important role in tumor invasion and metastasis. However, the specific mechanism by which TRAF6 promotes colorectal cancer (CRC) metastasis is incompletely understood. This study aimed to determine whether TRAF6 affects the LPS-NF-κB-VEGF-C signaling pathway through ubiquitination, which plays a role in colorectal cancer metastasis. Here, our results showed that TRAF6 affected lymphangiogenesis through the LPS-NF-κB-VEGF-C signaling pathway. Using ubiquitination experiments, we found that TRAF6 was mainly ubiquitinated with the K63-linked chains, and LPS promoted ubiquitination of TRAF6 and K63-linked chains. More importantly, TRAF6 124mut is the main ubiquitination site of TRAF6 interacting with K63-linked chains. TRAF6 affected the migration, invasion, and lymphatic metastasis of colorectal cancer through its ubiquitination. In subcutaneous xenograft models, TRAF6 124mut inhibited tumor growth. In conclusion, our results provide new insight for studying the mechanism of lymphangiogenesis in colorectal cancer to promote cancer metastasis, which may provide new ideas for tumor immunotherapy.

Extracorporeal Treatment for Gabapentin and Pregabalin Poisoning: Systematic Review and Recommendations From the EXTRIP Workgroup.

Toxicity from gabapentin and pregabalin overdose is commonly encountered. Treatment is supportive, and the use of extracorporeal treatments (ECTRs) is controversial. The EXTRIP workgroup conducted systematic reviews of the literature and summarized findings following published methods. Thirty-three articles (30 patient reports and 3 pharmacokinetic studies) met the inclusion criteria. High gabapentinoid extracorporeal clearance (>150mL/min) and short elimination half-life (<5 hours) were reported with hemodialysis. The workgroup assessed gabapentin and pregabalin as "dialyzable" for patients with decreased kidney function (quality of the evidence grade as A and B, respectively). Limited clinical data were available (24 patients with gabapentin toxicity and 7 with pregabalin toxicity received ECTR). Severe toxicity, mortality, and sequelae were rare in cases receiving ECTR and in historical controls receiving standard care alone. No clear clinical benefit from ECTR could be identified although major knowledge gaps were acknowledged, as well as costs and harms of ECTR. The EXTRIP workgroup suggests against performing ECTR in addition to standard care rather than standard care alone (weak recommendation, very low quality of evidence) for gabapentinoid poisoning in patients with normal kidney function. If decreased kidney function and coma requiring mechanical ventilation are present, the workgroup suggests performing ECTR in addition to standard care (weak recommendation, very low quality of evidence).

Primary care physicians' attitudes and knowledge regarding medical cannabis and willingness to prescribe it: the Israeli experience.

BACKGROUND: Use of medical cannabis (MC) in Israel has increased since its regulatory approval in 2016. Currently, more than 1% of Israeli adults are treated with MC; this requires primary care physicians (PCPs) to be familiar with this treatment option. OBJECTIVES: We assessed the attitudes and knowledge of Israeli PCPs toward MC and evaluated their willingness to prescribe it for different medical conditions. METHODS: A cross-sectional survey which was distributed to PCPs in Israel. Physicians were asked about their opinions, knowledge, and willingness to prescribe MC. RESULTS: Two hundred and one PCPs answered the questionnaire. Their average age was 47 years (±11.2), 71% were specialists. 51% of the respondents thought that MC is an effective treatment. 63% replied that they had little knowledge and 75% indicated that they would like to deepen it. 61% of the respondents were willing to initiate an MC treatment for a dying patient, while less than 50% were willing to initiate MC treatment for various other conditions. Most respondents indicated that they were willing to renew a prescription for any approved medical condition. Willingness to prescribe MC increased for physicians who agreed that MC was effective (odds ratio [OR] 21.9, 95% confidence interval [CI] 2.40-200.85), for physicians who strongly agreed with the statement that they had sufficient knowledge (OR 5.0, 95% CI 1.58-15.83) and for residents compared with specialists (OR 4.0, 95% CI 1.52-10.73). CONCLUSIONS: Our survey revealed PCPs' differing opinions and insufficient knowledge regarding treatment with MC. These findings suggest that continuing medical education regarding MC is needed.

Use of medical cannabis (MC) in Israel has increased substantially since its regulatory approval in 2016. Currently, more than 1% of Israeli adult population receive MC; this requires primary care physicians (PCPs) to be familiar with this treatment option. We assessed the attitudes and knowledge of Israeli PCPs toward MC and evaluated their willingness to prescribe it for different medical indications. Two hundred and one PCPs answered our questionnaire. 51% of the respondents thought that MC was an effective treatment. 63% of physicians stated that they had little knowledge regarding MC and 75% indicated that they would like to deepen it. 61% of the respondents were willing to initiate MC treatment for a dying patient, while less than 50% were willing to initiate MC treatment for other conditions. Willingness to initiate treatment with MC was low for most indications, while renewal was more acceptable. Our survey revealed PCPs' different opinions and insufficient knowledge regarding the utilization of MC in primary care. These findings emphasize the necessity for continuous medical education regarding MC.