PurposeThe miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC).MethodsAn open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death.ResultsFifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%.ConclusionsThe combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785

BACKGROUND & AIM: Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF)a biologics, are at high risk for vaccine-preventable infections. Their ability to mount adequate vaccine responses is unclear. The aim of the study was to assess serologic responses to messenger RNA-Coronavirus Disease 2019 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared with healthy controls (HCs). METHODS: Prospective, controlled, multicenter Israeli study. Subjects enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-Gastroenterology 2021;-:1-14 CLINICAL ATspike antibody levels and functional activity, anti-TNFa levels and adverse events (AEs) were detected longitudinally. RE-SULTS: Overall, 258 subjects: 185 IBD (67 treated with anti-TNFa, 118 non-anti-TNFa), and 73 HCs. After the first vaccine dose, all HCs were seropositive, whereas w7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFa treated compared with non-anti-TNFa treated patients, and HCs (both P < .001). Neutralizing and inhibitory functions were both lower in anti-TNFa treated compared with non-anti-TNFa treated patients, and HCs (P < .03; P < .0001, respectively). Anti-TNFa drug levels and vaccine responses did not affect anti-spike levels. Infection rate (w2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. CONCLUSIONS: In this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of BNT162b2; however, its magnitude was significantly lower in patients treated with anti-TNFa, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.

Earlier studies showed that two protein A complex enzyme system that catalyzes adenylylation and deadenylylation of Escherichia coli glutamine synthetase (EC 6.3.1.2) controls its activity and its response to metabolic effectors (1-7). A protein of molecular weight about 130,000, designated PI (5), catalyzes both adenylylation (reaction 1) and deadenylylation (reaction 2). glutamine synthetase + ATP -AMP-synthetase + PP1 (1) AMP-synthetase + Pi --ADP + glutamine synthetase (2) A second protein of molecular weight 50,000 designated PI,, stimulates (3, 5) reaction 2. As originally studied (3, 5, 7), PI, had no effect on reaction 1.We report here that PI, can exist in two forms. One, designated Pi,-DA, resembles the form previously described (5); it stimulates Pi-catalyzed deadenylylation (reaction 2) but has little effect on the adenylylation (reaction 1). The other form, designated P1i-AT, markedly stimulates reaction 1, but has little or no effect on reaction 2. In the presence of 2-oxoglutarate, UTP, and ATP, an enzyme present in preparations of P1 catalyzes the conversion of Pi,-AT to Pi,-DA. ['y-32P]UTP (3.5 Ci/mmol) was obtained from International Chemical and Nuclear Corp. The purity of all isotopic compounds was confirmed by thin-layer chromatography. Dithiothreitol (DTT) and 2-oxo glutarate were from Calbiochem. L-glutamine and iglutamate were from Sigma. All nucleotides were from P-L Biochemicals; Sephadex G-100 was from Pharmacia.Enzymes. Glutamine synthetase was purified by a zinc precipitation method (R. Miller and E. R. Stadtman, unpublished procedure) from E. coli W cells grown on a medium containing 75 mM NH4Cl and 0.67 M glycerol and harvested after several hours in the stationary phase. This enzyme contained an average of 0.8 equivalent of AMP per mole (E6-.8).The [14C]adenylylated glutamine synthetase, which served as a substrate for all the deadenylylation experiments, was prepared enzymatically (8) by adenylylation of Eo-with ['4C]ATP. The glutamine synthetase so prepared contained 11.4 equivalents of AMP per mole (E-i.i), with a specific activity of 20 cpm/pmol of adenylylated subunits.Partially purified preparations of PI and PI, were obtained (5) from E. coli W cells grown on a medium containing 0.67 M glycerol and either 38 or 76 mM NH4Cl. The cells were harvested about 12 hr after the onset of stationary phase. Purity of the PI and Pi,-preparations finally obtained was estimated to be about 40 and 70%O, respectively. Both enzymes were stable for several months when stored at -80°C in 20 mM Tris-0.5 MM DTT-0.25 mM Na2MgEDTA (pH 7.5).Enzyme Askat. The assay mixture (0.1 ml) for estimation of deadenylyllting activity (DA-activity) contained 50 mM 2-methylimidazole HCl (pH 7.2), 0.02 mM ATP, 1.0 mM UTP, 15 mM 2-oxoglutarate, 20 mM MgCl2, 5 mM NarMgEDTA, 20 mM K phosphate, 1 mM DTT, 100 ,ug of[I4C]ATP-adenylylated glutamine synthetase (equal to 2.0 nmol of adenylylated subunits, 20 X 101 cpm'nmol) and enzyme. After 30 min at 37°C, 0.15 ml of 6% HC104 was added and the mixtures were cen...

The purpose of this study was to evaluate ambulatory cancer patients' knowledge of their diagnosis and stage, their expectations of medical and nursing staff, and issues related to communication with the professional staff. A structured interview was conducted with each of 103 consecutive cancer patients attending the Oncology Day Hospital of the Shaare Zedek Medical Center. There were 77 women and 26 men, and their median age was 56 (18-86) years. Their religious status was elicited: 48% described themselves as religious, 25% as traditional, and 27% as secular. According to their physicians, 41 were in remission, 11 had stable disease, 47 had progressive disease and in 4 the disease status was unknown. Patients tended to underestimate the status of their disease: among those with progressive disease, 36% stated that their disease was stable or in remission. Overwhelmingly, patients expected that their oncologists should be patient and skilled in diagnostic procedures (98%), tactful, considerate and therapeutically skilled (90-95%), and skilled in the management of pain and the psychosocial consequences of cancer (75-85%). When there is bad news to be transmitted, 92% of patients indicated that they would want disclosure, while 6% indicated that they would want the news withheld from them but passed on to their family members. Most patients were very satisfied with the clarity of the information they received about their disease (85%) and the sensitivity with which it was transmitted (90%). Although 88% of patients reported that they relied on their oncologist for therapeutic decision making, 45% indicated that they had sought a second opinion and 32% reported seeking the opinion of a rabbinical medical broker. Almost all, 97%, of patients indicated that they felt comfortable seeking advice from their oncologist, and the oncologist was the staff member most often sought out for both information (69%) and support (66%). The data indicate high patient expectations of nursing and medical oncology staff members' skills and behaviors. Despite expressing a high level of satisfaction, a substantial percentage of patients had an inaccurate understanding of their disease status.