Dual enzymatic reactions were introduced to fabricate programmed gemcitabine (GEM) nanovectors for targeted pancreatic cancer therapy. Dual-enzyme-sensitive GEM nanovectors were prepared by conjugation of matrix metalloproteinase-9 (MMP-9) detachable poly(ethylene glycol) (PEG), cathepsin B-cleavable GEM, and targeting ligand CycloRGD to CdSe/ZnS quantum dots (QDs). The GEM nanovectors decorated with a PEG corona could avoid nonspecific interactions and exhibit prolonged blood circulation time. After GEM nanovectors were accumulated in tumor tissue by the enhanced permeability and retention (EPR) effect, the PEG corona can be removed by overexpressed MMP-9 in tumor tissue and RGD would be exposed, which was capable of facilitating cellular internalization. Once internalized into pancreatic cancer cells, the elevated lysosomal cathepsin B could further promote the release of GEM. By employing dual enzymatic reactions, the GEM nanovectors could achieve prolonged circulation time while maintaining enhanced cellular internalization and effective drug release. The proposed mechanism of the dual enzymatic reaction-assisted GEM delivery system was fully investigated both in vitro and in vivo. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2',2'-difluorodeoxyuridine (dFdU) could be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.

The objective of this study was to verify the safety of a new technique termed "binding pancreaticojejunostomy" in a prospective cohort study. Pancreaticojejunal anastomostic leakage is a major cause of morbidity and mortality after pancreaticoduodenectomy. To prevent the development of pancreatic fistulas, we designed a special technique that we termed binding pancreaticojejunostomy. Binding pancreaticojejunostomy entails binding 3 cm of the serosamuscular sheath of the jejunum to the intussuscepted pancreatic stump. From January 1996 to May 2001, a total of 150 consecutive patients were treated with this type of pancreaticojejunostomy, including typical pancreaticoduodenectomy in 120, hepatopancreaticoduodenectomy in 17, pylorus-preserving pancreaticoduodenectomy in 10, and duodenal-preserving resection of the head of the pancreas in three. None of the patients developed pancreatic fistulas. The overall morbidity was 31.3%. The following complications occurred: gastrointestinal bleeding in six, pulmonary infection in 12, wound infection in 20, delayed gastric emptying in three, incision dehiscence in four, and hepatic insufficiency in two. The mean postoperative hospital stay was 19.8 +/- 5 days. Binding pancreaticojejunostomy is a safe, simple, and effective technique.

Our results indicate that the combination of VNN1 and MMP9 may be used as a novel blood biomarker panel for the discrimination of pancreatic cancer-associated diabetes from type 2 diabetes.

Reduced food intake is common to many pathological conditions, such as infection and toxin exposure. However, cortical circuits that mediate feeding responses to these threats are less investigated. The anterior insular cortex (aIC) is a core region that integrates interoceptive states and emotional awareness and consequently guides behavioral responses. Here, we demonstrate that the right-side aIC CamKII+ (aICCamKII) neurons in mice are activated by aversive visceral signals. Hyperactivation of the right-side aICCamKII neurons attenuates food consumption, while inhibition of these neurons increases feeding and reverses aversive stimuli-induced anorexia and weight loss. Similar manipulation at the left-side aIC does not cause significant behavioral changes. Furthermore, virus tracing reveals that aICCamKII neurons project directly to the vGluT2+ neurons in the lateral hypothalamus (LH), and the right-side aICCamKII-to-LH pathway mediates feeding suppression. Our studies uncover a circuit from the cortex to the hypothalamus that senses aversive visceral signals and controls feeding behavior.

Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune nervous system disease that has become increasingly recognized. This retrospective study is aimed to analyze the relations between clinical manifestations and blood brain barrier (BBB) integrity in anti-NMDAR encephalitis patients. Methods: Anti-NMDAR encephalitis patients were admitted to the First Affiliated Hospital of Guangxi Medical University from April 2014 to April 2020. Patients were grouped by the normal BBB and damaged BBB groups according to the cerebrospinal fluid (CSF) albumin/serum albumin (QAlb). Neutrophil-to-lymphocyte ratio (NLR) in peripheral blood was used for estimating the inflammatory status. The modified Rankin Scale (mRS) was used to assess prognosis. Results: Seventy-three anti-NMDAR encephalitis patients were diagnosed based on the autoimmune encephalitis diagnosis criteria of 2016. Fifty-three (72.6%) patients were in the normal BBB group and twenty (27.4%) were in the BBB damaged group. There were no significant differences in gender, age, psychiatric disturbances, epilepsy, speech disorder, motor dysfunction, memory dysfunction, and autonomic dysfunction between the two groups (p>0.05). Nevertheless, the proportions of decreased consciousness, ICU admission, NLR, CSF protein and intrathecal IgG synthesis (IgGIF, IgGLoc) in the damaged BBB group were higher than that in the normal BBB group (p<0.05). Patients (79.2%) with normal BBB had good prognosis compared to patients with damaged BBB (50%) after 2 months follow-up. The median mRS before and after immunotherapy in the damaged BBB group were significantly higher than that in the normal BBB group (p<0.01, p<0.05, respectively). Additionally, QAlb increased was positively correlated with the quantitative intrathecal IgG synthesis (IgGLoc: r=0.66; IgGIF: r=0.433, all p<0.001). Conclusion: The dysfunction of BBB can be helpful in evaluating its prognosis since QAlb showed associations with ICU admission, NLR, a higher CSF protein, intrathecal IgG synthesis (IgGLoc, IgGIF) and mRS score after 2 months follow-up.