Lanthanum chloride exerts therapeutic potential for chronic kidney disease by suppressing nanohydroxyapatite-induced mitophagy and mitochondria-mediated apoptosis.

OBJECTIVE: To investigate the protective effect of lanthanum chloride on kidney injury in chronic kidney disease and its mechanism. METHODS: 1. Patients with CKD stage 2-5 were selected to analyze the effect of lanthanum-containing preparations on CKD. 2. Sixty healthy male Wistar rats were randomly divided into control group, model group, lanthanum chloride groups (0.03 ng/kg, 0.1 ng/kg, 0.3 ng/kg, q.3d., i.v.), and lanthanum carbonate group (0.3 g/kg, q.d., p.o.). The model group was given 2 % adenine suspension (200 mg/kg, q.d., p.o.) for the first two weeks, followed by adenine (200 mg/kg, b.i.d., p.o.) for 2 weeks, and all animals were sacrificed after eight weeks of administration. 3. The serum and kidneys of rats in each group were collected to detect the oxidative stress indicators and the expressions of LC3B-Ⅱ/Ⅰ, p62, Bcl-2, Bax, Caspase-3 and Cleaved Caspase-3. 4. Human renal tubular epithelial cells (HK-2 cells) were divided into control group, model group, lanthanum chloride group, pyrophosphate (PPI) group, chloroquine (CQ) group, rapamycin group, doxorubicin (DOX) group and N-acetyl-L-cysteine (NAC) group. The mitochondrial status, mitophagy and apoptosis levels were detected. RESULTS: 1.Lanthanum-containing preparations can significantly reduce the biochemical indexes of kidney injury in patients with CKD. 2. In the model group, the glomerular and renal tubular edema, the mitochondria were short and round, and the expression of LC3B-Ⅱ/Ⅰ and Bax increased, while the expression of P62, Bcl-2 and Caspase-3 decreased, and there was a significant improvement in the administration group, especially the 0.1 ng/kg group and lanthanum carbonate group. 3. In the HK-2 cell model group, mitochondrial membrane potential decreased, morphology changed and the results were reversed by lanthanum chloride. CONCLUSION: Lanthanum chloride may alter the morphology of nano-hydroxyapatite, thereby inhibiting its induced mitophagy and mitochondria-mediated apoptosis, and ultimately improve CKD renal injury effectively.

EGFR and EGFRvIII coopt host defense pathways, promoting progression in glioblastoma.

BACKGROUND: Co-amplification of EGFR and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma. METHODS: We used phospho-proteomics, RNA-sequencing, TCGA data and glioblastoma cell culture and mouse models to study the signal transduction mediated by EGFR and EGFRvIII. RESULTS: We report that EGFR and EGFRvIII stimulate the innate immune defense receptor Toll-like Receptor 2 (TLR2); and that knockout of TLR2 dramatically improved survival in orthotopic glioblastoma xenografts. EGFR and EGFRvIII activated TLR2 in a ligand-independent manner, promoting tumor growth and immune evasion. We show that EGFR and EGFRvIII cooperate to activate the Rho-associated protein kinase ROCK2, which modulated malignant progression both by activating TLR2 and WNT signaling, and through remodeling the tumor microenvironment. CONCLUSION: Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-ß-catenin/TLR2 signaling pathways.

The role of SEMG1 overexpression in OSCC tumorigenesis and its relation with metabolic molecules.

OBJECTIVES: This study aimed to investigate the expression and biological significance of Semenogelin 1 (SEMG1), a member of the cancer-testis antigen family, in oral squamous cell carcinoma (OSCC). Further, we explored its potential association with metabolism-related molecules. METHODS: SEMG1 expression levels in OSCC were determined through immunohistochemistry, flow cytometry, and Western blot analyses. To decipher the biological implications of SEMG1 in OSCC, the CAL27 OSCC cell line was either stably overexpressed with SEMG1 or subjected to SEMG1-shRNA knockdown. The relationship between clinicopathological parameters and SEMG1 expression in OSCC patients was also assessed. RESULTS: SEMG1 was found to be overexpressed in OSCC, though its expression was not influenced by the pathological grade. The fluorescent dihydroethidium assay indicated that SEMG1 augmented reactive oxygen species production. The mitochondrial membrane potential assay suggested a significant upregulation of mitochondrial membrane potential by SEMG1. Cell cycle assessments highlighted that SEMG1 overexpression led to a notable rise in cells entering the S-phase. Additionally, a strong correlation between SEMG1 expression and both ENO1 and PKM2 expression in OSCC was observed. CONCLUSIONS: The findings underscore the elevated expression of SEMG1 in OSCC and its contributory role in the tumorigenesis of OSCC patients.

Probiotics functionalized with a gallium-polyphenol network modulate the intratumor microbiota and promote anti-tumor immune responses in pancreatic cancer.

The intratumor microbiome imbalance in pancreatic cancer promotes a tolerogenic immune response and triggers immunotherapy resistance. Here we show that Lactobacillus rhamnosus GG probiotics, outfitted with a gallium-polyphenol network (LGG@Ga-poly), bolster immunotherapy in pancreatic cancer by modulating microbiota-immune interactions. Upon oral administration, LGG@Ga-poly targets pancreatic tumors specifically, and selectively eradicates tumor-promoting Proteobacteria and microbiota-derived lipopolysaccharides through a gallium-facilitated disruption of bacterial iron respiration. This elimination of intratumor microbiota impedes the activation of tumoral Toll-like receptors, thus reducing immunosuppressive PD-L1 and interleukin-1ß expression by tumor cells, diminishing immunotolerant myeloid populations, and improving the infiltration of cytotoxic T lymphocytes in tumors. Moreover, LGG@Ga-poly hampers pancreatic tumor growth in both preventive and therapeutic contexts, and amplifies the antitumor efficacy of immune checkpoint blockade in preclinical cancer models in female mice. Overall, we offer evidence that thoughtfully designed biomaterials targeting intratumor microbiota can efficaciously augment immunotherapy for the challenging pancreatic cancer.

Fanlian Huazhuo Formula alleviates high-fat diet-induced non-alcoholic fatty liver disease by modulating autophagy and lipid synthesis signaling pathway.

BACKGROUND: Fanlian Huazhuo Formula (FLHZF) has the functions of invigorating spleen and resolving phlegm, clearing heat and purging turbidity. It has been identified to have therapeutic effects on type 2 diabetes mellitus (T2DM) in clinical application. Non-alcoholic fatty liver disease (NAFLD) is frequently diagnosed in patients with T2DM. However, the therapeutic potential of FLHZF on NAFLD and the underlying mechanisms need further investigation. AIM: To elucidate the effects of FLHZF on NAFLD and explore the underlying hepatoprotective mechanisms in vivo and in vitro. METHODS: HepG2 cells were treated with free fatty acid for 24 hours to induce lipid accumulation cell model. Subsequently, experiments were conducted with the different concentrations of freeze-dried powder of FLHZF for 24 hours. C57BL/6 mice were fed a high-fat diet for 8-week to establish a mouse model of NAFLD, and then treated with the different concentrations of FLHZF for 10 weeks. RESULTS: FLHZF had therapeutic potential against lipid accumulation and abnormal changes in biochemical indicators in vivo and in vitro. Further experiments verified that FLHZF alleviated abnormal lipid metabolism might by reducing oxidative stress, regulating the AMPKα/SREBP-1C signaling pathway, activating autophagy, and inhibiting hepatocyte apoptosis. CONCLUSION: FLHZF alleviates abnormal lipid metabolism in NAFLD models by regulating reactive oxygen species, autophagy, apoptosis, and lipid synthesis signaling pathways, indicating its potential for clinical application in NAFLD.

Dysbiosis promotes recurrence of adenomatous polyps in the distal colorectum.

BACKGROUND: Colorectal polyps, which are characterized by a high recurrence rate, represent preneoplastic conditions of the intestine. Due to unclear mechanisms of pathogenesis, first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection. Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps, the exact compositions and roles of bacteria in the mucosa around the lesions, rather than feces, remain unsettled. AIM: To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps. METHODS: Mucosal samples were collected from four patients consistently with adenomatous polyps (Ade), seven consistently with non-Ade (Pol), ten with current Pol but previous Ade, and six healthy individuals, and bacterial patterns were evaluated by 16S rDNA sequencing. Linear discriminant analysis and Student's t-tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes. Pearson's correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators. RESULTS: The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals. These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps, but also existed in histologically normal tissue 10 cm distal from the lesions. Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions, Pol, and Ade. Increased abundance of Gram-negative bacteria, including Klebsiella, Plesiomonas, and Cronobacter, was observed in Pol group and Ade group, suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment. Meanwhile, age and gender were linked to bacteria changes, indicating the potential involvement of sex hormones. CONCLUSION: These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps, especially adenoma. Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.

Characteristics of patients with difficult-to-treat rheumatoid arthritis: a descriptive retrospective cohort study.

BACKGROUND: In 2021, an EULAR task force published a definition of difficult-to-treat rheumatoid arthritis (D2T RA). Our current knowledge of D2T RA with the EULAR definition is based on European and Asian cohorts, and no North American cohort has yet to be published. The aim of this study was to compare D2T RA patients to non-D2T RA who are good responders to advanced therapy, and to describe their evolution in an university health center patient cohort. METHODS: This is a retrospective single centre study of the medical records of all adults with RA on at least one biologic or target synthetic DMARD (b/tsDMARD). D2T RA group was defined according to the EULAR definition of D2T RA. The non-D2T RA group was defined as a b/tsDMARD good responder who had low-disease activity or remission for at least one year on 1 or 2 b/tsDMARD mechanism of action. We compared the patients' comorbidities, and history of b/tsDMARD use. Descriptive statistics and proportions were calculated. Kaplan-Meier analysis with log-rank test was used to estimate and compare median survival. RESULTS: Among the 417 patients, 101 (24%) were D2T RA and 316 (76%) were non-D2T RA. D2T RA group was slightly younger (63 ± 9 years versus 65 ± 12 years, p = 0.045), more likely to have concomitant non-inflammatory pain (28% versus 8%, p < 0.0001) and to discontinue at least one b/tsDMARD due to intolerance (39% versus 10%, p < 0.0001). In the D2T RA group, JAK inhibitors were associated with longer drug continuation when used as the third b/tsDMARD. Fewer patients were using corticosteroid at their most recent follow-up in this Canadian cohort compared to others (16% versus from 29 to 74%). CONCLUSION: Concomitant non-inflammatory pain was more prevalent in D2T RA patients compared to b/tsDMARD good responder non-D2T RA patients. Steroid-sparing strategies is possible even in D2T RA patients. Future prospective research may compare JAK inhibitors with other mechanisms of action in D2T RA.

Safety of low-intensity extracorporeal shock wave therapy in prostate disorders: in vitro and in vivo evidence.

ABSTRACT: Recent evidence suggests that low-intensity extracorporeal shock wave therapy (Li-ESWT) is a promising treatment for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); however, its safety in pelvic organs, particularly prostate tissues and cells, remains unclear. The current study evaluates the risks of prostate cell damage or oncogenesis following the administration of Li-ESWT for prostatitis. To this end, a robust in vitro model (Cell Counting Kit-8 [CCK-8] assay, clone formation assay, cell scratch assay, lactate dehydrogenase [LDH] release assay, flow cytometry, and immunoblotting assay) was designed to examine the effects of Li-ESWT on cell proliferation, clonogenicity, migration, membrane integrity, and DNA damage. Exome sequencing of Li-ESWT-treated cells was performed to determine the risk of carcinogenesis. Furthermore, an in vivo rat model ( n = 20) was employed to assess the effects of Li-ESWT on cancer biomarkers (carcinoembryonic antigen [CEA], Ki67, proliferating cell nuclear antigen [PCNA], and gamma-H2A histone family member X, phosphorylation of the H2AX Ser-139 [ γ -H2AX]) in prostate tissue. Based on our findings, Li-ESWT promotes cellular growth and motility without inducing significant cell membrane or DNA damage or alterations. Genetic analyses did not demonstrate an increase in mutations, and no damage to prostate tissue or upregulation of cancer biomarkers was detected in vivo. This comprehensive in vitro and in vivo assessment confirms the safety of Li-ESWT in managing prostate disorders.

Sialidase-Chimeric Bioengineered Bacteria for Tumor-Sialoglycan-Triggered Solid Tumor Therapy.

Adoptive cell therapies for solid tumors are usually limited by off-target antigens, incapable tissue infiltration, and cell function exhaustion. In contrast, bacterial cells possess the inherent competencies of preferential tumor targeting, deep tissue penetration, and high intratumoral bioactivity and represent promising alternatives to overcome these challenges. Here, a sialic-acid-responsive regulatory gene circuit is engineered into Escherichia coli MG1655 to express cytolysin of hemolysin E (HlyE). Furthermore, sialidases are bioorthogonally decorated onto the surface of azido-functionalized bioengineered bacteria for recognizing tumor sialoglycans and cleaving their sialosides into free sialic acids. As chemical inducers, sialic acids feedbackingly activate the bacterial gene circuit to produce HlyE and lyse tumor cells. This study mimics the tumor antigen-induced cytotoxin production and cell lysis that occurs in chimeric antigen receptor T (CAR-T) cells yet surmounts the intrinsic limitations of adoptive cell therapies. Moreover, sialidase-mediated tumor cell desialylation also reverses the immunosuppressive effect of glycoimmune checkpoints and further improves the therapeutic effect of solid tumors.

The Effects of Pulmonary Artery Catheter on the Short-Term Outcomes of Patients Undergoing Off-Pump Coronary Artery Bypass Grafting: A Single-Center Retrospective Study.

Background: Pulmonary artery catheters (PAC) are widely used in patients undergoing off-pump coronary artery bypass (OPCAB) grafting surgery. However, primary data suggested that the benefits of PAC in surgical settings were limited. Therefore, the present study sought to estimate the effects of PAC on the short-term outcomes of patients undergoing OPCAB surgery. Methods: The characteristics, intraoperative data, and postoperative outcomes of consecutive patients undergoing primary, isolated OPCAB surgery from November 2020 to December 2021 were retrospectively extracted. Patients were divided into two groups (PAC and no-PAC) based on PAC insertion status. Data were analyzed with a 1:1 nearest-neighbor propensity score matched-pair in PAC and no-PAC groups. Results: Of the 1004 Chinese patients who underwent primary, isolated OPCAB surgery, 506 (50.39%) had PAC. Propensity score matching yielded 397 evenly balanced pairs. Compared with the no-PAC group (only implanted a central venous catheter), PAC utilization was not associated with improved in-hospital mortality in the entire or matched cohort. Still, the matched cohort showed that PAC utilization increased epinephrine usage and hospital costs. Conclusions: The current study demonstrated no apparent benefit or harm for PAC utilization in OPCAB surgical patients. In addition, PAC utilization was more expensive.

Integrated multi-omics analyses revealed the association between rheumatoid arthritis and colorectal cancer: MYO9A as a shared gene signature and an immune-related therapeutic target.

BACKGROUND: Our study aims to explore the relationship, shared gene signature, and the underlying mechanisms that connect rheumatoid arthritis (RA) to colorectal cancer (CRC). METHODS: Mendelian randomization (MR) analysis was conducted to assess the causality between RA and CRC. Summary statistic data-based Mendelian randomization (SMR) leveraging eQTL data was employed to identify the CRC-related causal genes. Integrated analyses of single-cell RNA sequencing and bulk RNA sequencing were employed to comprehensively investigate the shared gene signature and potential mechanisms underlying the pathogenesis of both RA and CRC. Predictive analysis of the shared hub gene in CRC immunotherapy response was performed. Pan-cancer analyses were conducted to explore the potential role of MYO9A in 33 types of human tumors. RESULTS: MR analysis suggested that RA might be associated with a slight increased risk of CRC (Odds Ratio = 1.04, 95% Confidence Interval = 1.01-1.07, P = 0.005). SMR analysis combining transcriptome analyses identified MYO9A as a causal gene in CRC and a shared gene signature in both RA and CRC. MYO9A may contribute to tumor suppression, while downregulation of MYO9A may impact CRC tumorigenesis by disrupting epithelial polarity and architecture, resulting in a worse prognosis in CRC. Additionally, MYO9A shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Pan-cancer analyses demonstrated MYO9A may have a protective role in the occurrence and progression of various human cancers. CONCLUSION: RA might be associated with a slight increased risk of CRC. MYO9A is a shared gene signature and a potential immune-related therapeutic target for both CRC and RA. Targeting the MYO9A-mediated loss of polarity and epithelial architecture could be a novel therapeutic approach for CRC.

Proteomic profile of tissue-derived extracellular vesicles from benign odontogenic lesions.

BACKGROUND: Benign odontogenic lesions (BOLs) can cause severe jaw bone defects and compromise the quality of life of patients. Extracellular vesicles (EVs) are well-established and versatile players in mediating pathophysiological events. EVs in the interstitial space (tissue-derived EVs or Ti-EVs) possess higher specificity and sensitivity in disease-related biomarker discovery. However, the role of Ti-EV-loaded proteins in mediating the development of BOLs has remained untapped. Herein, we aim to explore the contribution of Ti-EV-loaded proteins to the development of BOLs. METHODS: Samples were obtained from 3 with dental follicle, 3 with dentigerous cyst (DC), 7 with odontogenic keratocyst (OKC), and 3 patients with ameloblastoma (AM). Tissue-derived EVs were then extracted, purified, and validated using ultracentrifugation, transmission electron microscopy, and western blotting. Proteins from Ti-EVs were analyzed using LC-ESI tandem mass spectroscopy and differentially expressed proteins were screened, which was then validated by immunohistochemistry and immunofluorescence assays. RESULTS: The protein profile of Ti-EVs in each group was mapped by LC-MS analysis. The top 10 abundant proteins in BOL-derived Ti-EVs were COL6A3, COL6A1, ALB, HIST1H4A, HBB, ACTB, HIST1H2BD, ANXA2, COL6A2 and FBN1. Additionally, unique proteins in the Ti-EVs from various lesions were identified. Moreover, focal adhesion kinase (FAK) and myeloid differentiation primary response 88 (MyD88) showed higher expressions in Ti-EVs derived from OKC and AM, which were confirmed by immunohistochemistry and immunofluorescence staining. CONCLUSIONS: Ti-EVs containing FAK and MyD88 might be related to the development of OKC and AM, which can be potential therapeutic targets.

Effect of LRRC15 on autophagy in A549 cells.

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, and irreversible interstitial lung disease with unknown cause. To explore the role and regulatory mechanism of leucine-rich repeat-containing protein 15 (LRRC15) in IPF, bleomycin (BLM)-induced pulmonary fibrosis in mouse and A549 cells were constructed, and the expression of LRRC15 were detected. Then, MTT, GFP-RFP-LC3 dual fluorescent labeling system and Western blotting were used to investigate the effects of LRRC15 on cell activity and autophagy after transfection of siLRRC15, respectively. The results indicated that the expression of LRRC15 was significantly increased after the BLM treatment in mouse lung tissue and A549 cells. The designed and synthesized siLRRC15 followed by transfection into A549 cells resulted in a dramatic reduction in LRRC15 expression and partially restored the cell damage induced by BLM. Moreover, the expression of LC3-II and P62 were up-regulated, the amount of autophagosome were increased by GFP-RFP-LC3 dual fluorescent labeling assay after BLM treatment. Meanwhile, this study also showed that the key autophagy proteins LC3-II, ATG5 and ATG7 were up-regulated, P62 was down-regulated and autophagic flux were enhanced after further treatment of A549 cells with siLRRC15. The above findings suggest that LRRC15 is an indicator of epithelial cell damage and may participate in the regulation of fibrosis through autophagy mechanism in IPF. This study provides necessary theoretical basis for further elucidating the mechanism of IPF.

Bacterial Biohybrids for Invasion of Tumor Cells Promote Antigen Cross-Presentation Through Gap Junction.

Due to inherent differences in cellular composition and metabolic behavior with host cells, tumor-harbored bacteria can discriminatorily affect tumor immune landscape. However, the mechanisms by which intracellular bacteria affect antigen presentation process between tumor cells and antigen-presenting cells (APCs) are largely unknown. The invasion behavior of attenuated Salmonella VNP20009 (VNP) into tumor cells is investigated and an attempt is made to modulate this behavior by modifying positively charged polymers on the surface of VNP. It is found that non-toxic chitosan oligosaccharide (COS) modified VNP (VNP@COS) bolsters the formation of gap junction between tumor cells and APCs by enhancing the ability of VNP to infect tumor cells. On this basis, a bacterial biohybrid is designed to promote in situ antigen cross-presentation through intracellular bacteria induced gap junction. This bacterial biohybrid also enhances the expression of major histocompatibility complex class I molecules on the surface of tumor cells through the incorporation of Mdivi-1 coupled with VNP@COS. This strategic integration serves to heighten the immunogenic exposure of tumor antigens; while, preserving the cytotoxic potency of T cells. A strategy is proposed to precisely controlling the function and local effects of microorganisms within tumors.

Application of PRI-E-a combined learning method in oral and maxillofacial oncology education.

The traditional lecture-based learning (LBL) method is facing great challenges due to its low efficiency and single proceeding form. We designed a PRI-E learning mode that combined and modified problem-based, case-based, and evidence-based learning with a step-by-step approach. We evaluated the practical learning outcomes of using the PRI-E mode by comparing it with traditional lecture-based learning in oral and maxillofacial oncology education. "PRI-E" consists of the first letters of the English words Passion, Research, Innovation, and Education, and it means "the best Education". This prospective randomized controlled trial included 40 participants. We evenly divided the participants into the PRI-E (n = 20) and LBL group (n = 20) based on the entrance test scores. The same staff group designed and then taught the learning content with different group measures. The evaluation included the final test scores and questionnaire assessments. Without affecting the examination results, the PRI-E teaching method was more satisfactory and popular with participants in terms of ability development and classroom participation. Enacting the PRI-E teaching method required more time, but this did not affect its popularity among the participants. Compared with the LBL learning mode, the PRI-E learning mode was more organized and efficient in oral and maxillofacial oncology education without affecting academic performance. This model has a high degree of satisfaction, which is conducive to training students' comprehensive ability.

Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

Exploiting BRAF mutations in the therapeutic approach towards oral and maxillofacial tumors.

Oral and maxillofacial tumors pose a significant clinical challenge due to their tendency to recur, despite advancements in surgical removal techniques. The jaw's intricate structure further complicates treatments and affects patient quality of life. Consequently, emphasis has shifted towards pharmacological interventions, to potentially reduce invasive surgical procedures. One promising approach targets BRAF mutations, specifically the common V600E mutation. BRAF, a critical protein kinase, regulates cell growth and differentiation via the RAS-RAF-MEK-ERK-MAP kinase pathway. A specific nucleotide change at position 1799, swapping Thymine (T) for Adenine (A), results in the V600E mutation, causing unchecked cell growth. This mutation is common in certain oral and maxillofacial tumors like ameloblastoma. A recent neoadjuvant therapy targeting BRAF, involving the use of dabrafenib and trametinib, has showcased a promising, safe, and effective strategy for organ preservation in the treatment of mandibular ameloblastoma. This convergence of molecular insights and targeted therapies holds the key to managing BRAF-mutated oral and maxillofacial tumors effectively, promising improved patient outcomes.

Proteomics study of bone tissue around ameloblastoma and the potential mechanism of CD36 in bone remodelling.

Ameloblastoma (AM) is characterised by local aggressiveness and bone resorption. To our knowledge, the proteomic profile of bone adjacent to AM has not previously been explored. We therefore looked at the differential proteins in cancellous bone (CB) adjacent to AM and normal CB from the mandible. CB proteins were extracted, purified, quantified, and analysed by liquid chromatography-mass spectrometry (LC-MS) using samples from five patients with AM. These proteins were further investigated using gene ontology for additional functional annotation and enrichment. Proteins that met the screening requirements of expression difference ploidy > 1.5-fold (upregulation and downregulation) and p < 0.05 were subsequently deemed differential proteins. Immunohistochemical staining was performed to confirm the above findings. Compared with normal mandibular CB, 151 differential proteins were identified in CB adjacent to the mandibular AM. These were mainly linked to cellular catabolic processes, lipid metabolism, and fatty acids (FA) metabolism. LC-MS and immunohistochemistry showed that CD36 was one of the notably decreased proteins in CB bordering the AM compared with normal mandibular CB (p = 0.0066 and p = 0.0095, respectively). CD36 expression in CB correlates with bone remodelling in AM, making CD36 a viable target for therapeutic approaches.

Efficacy and safety of different chemotherapy regimens combined with thalidomide in the treatment of diagnosed HIV-associated diffuse large B-cell lymphoma.

Objective: To investigate the short-term efficacy and safety of different chemotherapy regimens combined with thalidomide, in the treatment of low-income patients with newly diagnosed HIV-associated diffuse large B-cell lymphoma. Methods: A retrospective analysis was performed on 42 patients with HIV-DLBCL who were admitted to the Infectious Diseases Department of Yunnan Provincial Infectious Diseases Hospital from January 2018 to December 2020. 14 cases (including 1 case in stage II and 13 cases in stage III/IV) were treated with R-CHOP, 24 cases (including 1 case in stage II and 23 cases in stage III/IV) were treated with R-DAEPOCH, and 4 cases (including 1 case in stage II and 3 cases in stage III/IV) were treated with EPOCH. All patients were treated with thalidomide. The ART regimen was adjusted. At least 1 and up to 6 intrathecal injections were given during chemotherapy, and cotrimoxazole was taken orally to prevent infection. The clinical efficacy was evaluated after 4 cycles of chemotherapy, and adverse events were evaluated at each cycle of chemotherapy. Results: All patients received 1-8 cycles of chemotherapy. CR (64.2 %) was achieved in 9 patients in R-CHOP group, and 5 patients died. In the R-DAEPOCH group, 17 patients achieved CR (70.8 %) and 7 died. In the EPOCH group, 2 patients reached CR (50 %) and 2 died. The main adverse reactions were grade II and above myelosuppression. Conclusion: Combined treatment with thalidomide can improve the prognosis of low-income patients with newly diagnosed HIV-DLBCL.