Targeting Telomere Dynamics as an Effective Approach for the Development of Cancer Therapeutics.

Telomere is a protective structure located at the end of chromosomes of eukaryotes, involved in maintaining the integrity and stability of the genome. Telomeres play an essential role in cancer progression; accordingly, targeting telomere dynamics emerges as an effective approach for the development of cancer therapeutics. Targeting telomere dynamics may work through multifaceted molecular mechanisms; those include the activation of anti-telomerase immune responses, shortening of telomere lengths, induction of telomere dysfunction and constitution of telomerase-responsive drug release systems. In this review, we summarize a wide variety of telomere dynamics-targeted agents in preclinical studies and clinical trials, and reveal their promising therapeutic potential in cancer therapy. As shown, telomere dynamics-active agents are effective as anti-cancer chemotherapeutics and immunotherapeutics. Notably, these agents may display efficacy against cancer stem cells, reducing cancer stem levels. Furthermore, these agents can be integrated with the capability of tumor-specific drug delivery by the constitution of related nanoparticles, antibody drug conjugates and HSA-based drugs.

A new TROP2-targeting antibody-drug conjugate shows potent antitumor efficacy in breast and lung cancers.

Trophoblast cell surface antigen 2 (Trop2) is considered to be an attractive therapeutic target in cancer treatments. We previously generated a new humanized anti-Trop2 antibody named hIMB1636, and designated it as an ideal targeting carrier for cancer therapy. Lidamycin (LDM) is a new antitumor antibiotic, containing an active enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). AE and LDP can be separated and reassembled, and the reassembled LDM possesses cytotoxicity similar to that of native LDM; this has made LDM attractive in the preparation of gene-engineering drugs. We herein firstly prepared a new fusion protein hIMB1636-LDP composed of hIMB1636 and LDP by genetic engineering. This construct showed potent binding activities to recombinant antigen with a KD value of 4.57 nM, exhibited binding to Trop2-positive cancer cells and internalization and transport to lysosomes, and demonstrated powerful tumor-targeting ability in vivo. We then obtained the antibody-drug conjugate (ADC) hIMB1636-LDP-AE by molecular reconstitution. In vitro, hIMB1636-LDP-AE inhibited the proliferation, migration, and tumorsphere formation of tumor cells with half-maximal inhibitory concentration (IC50) values at the sub-nanomolar level. Mechanistically, hIMB1636-LDP-AE induced apoptosis and cell-cycle arrest. In vivo, hIMB1636-LDP-AE also inhibited the growth of breast and lung cancers in xenograft models. Moreover, compared to sacituzumab govitecan, hIMB1636-LDP-AE showed more potent antitumor activity and significantly lower myelotoxicity in tumors with moderate Trop2 expression. This study fully revealed the potent antitumor efficacy of hIMB1636-LDP-AE, and also provided a new preparation method for LDM-based ADC, as well as a promising candidate for breast cancer and lung cancer therapeutics.

Snake-shaped ePTFE nasal tip graft combined with conchal cartilage in Asian rhinoplasty: a retrospective cohort study.

BACKGROUND: Lacking a nasal tip projection is a common deformity of Asian nasals. Various commonly used nasal tip grafts require dissecting septal perichondrium, most of them are autologous cartilage with a nonintegrated design. A snake-shaped expanded polytetrafluoroethylene (ePTFE) nasal tip graft is an integrated, stable tip graft without any additional assembly and splicing, conforming to the nasal anatomy characteristics of Asians. METHOD: A retrospective study was performed on Asian patients who underwent rhinoplasty in the nasal tip at Peking University Third Hospital from 2015 to 2022. Nasal tip grafts were categorized into three groups: snake-shaped ePTFE combined with conchal cartilage (n = 15), only costal cartilage (n = 25), and only conchal cartilage (n = 17). Patients were excluded if their rhinoplasty did not involve any of the grafts above. Visual Analogue Scale, FACE-Q Nose, FACE-Q Nostril, Nasal Obstruction Symptom Evaluation scale, and Rhinoplasty Outcome Evaluation scale were used to evaluate the preoperative and postoperative results. RESULTS: Fifty-three (93.0%) cases had low nasal dorsum and 46 (80.7%) cases had short nose. There was no significant difference in complication rates among the three groups. The difference between preoperative and postoperative scale scores was statistically significant among the three groups (p < 0.05). Score improvements, including all scales, were the highest in the costal cartilage group and lowest in the conchal cartilage group. CONCLUSIONS: Snake-shaped ePTFE nasal tip grafts can be an effective integrated alternative that provides long-term safety and efficacy compared with traditional autogenous implants (conchal and costal cartilages).

Clinical value of the expression levels of tumor protein D52 and miR-133a on prognosis assessment of pancreatic cancer surgery.

Objective: To investigate the clinical value of the expression levels of tumor protein D52 (TPD52) and miR-133a on the prognosis assessment of pancreatic cancer surgery. Methods: This was a retrospective study. Ninety-seven patients who underwent radical surgery for pancreatic cancer in Cangzhou Central Hospital from January 2018 to January 2022 were selected and divided into four groups: TPD52 high expression group, TPD52 low expression group, miR-133a high expression group and miR-133a low expression group. The relationship between the expression levels of TPD52 and miR-133a and the clinicopathological features of patients with pancreatic cancer was analyzed. The COX regression model was used to analyze the risk factors affecting the prognosis of patients with pancreatic cancer. Results: The high expression rate of TPD52 and the low expression rate of miR-133a in pancreatic cancer tissues were higher than those in normal paracancerous tissues(P<0.05). Based on the comparison of prognosis and survival, the median survival time of patients with high expression of TPD52 and low expression of miR-133a was lower than that of patients with low expression of TPD52 and high expression of miR-133a, with a statistically significant difference(P<0.05). Moreover, multivariate Cox regression analysis showed that low differentiation of pancreatic cancer, III-IV stage of TNM, high expression of TPD52, as well as low expression of miR-133a were independent risk factors for postoperative survival of patients with pancreatic cancer(P<0.05). Conclusion: TPD52 is expressed at a high level whereas miR-133a at a low level in pancreatic cancer tissues, both of which together with low differentiation of pancreatic cancer and III-IV stage of TNM constitute independent risk factors affecting the surgical prognosis of patients with pancreatic cancer.

Late-stage modification of complex drug: Base-controlled Pd-catalyzed regioselective synthesis and bioactivity of arylated osimertinibs.

Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed C─H arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (K2CO3) promoted the arylation of acrylamide terminal C(sp2)-H, affording 34 derivatives. Conversely, sodium tert-butoxide (t-BuONa) mediated the aryl C(sp2)-H arylation of the indole C2 position, providing 27 derivatives. The derivative 3r containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFRT790M/L858R and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a "one substrate-multi reactions-multiple products" strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.

Effects of KLF11 on Vascular Smooth Muscle Cells and its Underlying Mechanisms in Intracranial Aneurysm.

Vascular smooth muscle cells (VSMCs) affect the phenotypic changes in intracranial aneurysm (IA). They exhibit enhanced dissociation and migration and play a key role in IA pathogenesis. KLF transcription factor 11 (KLF11), a member of the KLF family, significantly affects the cancer cell proliferation, differentiation, and apoptosis. However, its expression, biological functions, and latent action mechanisms in IA remain unclear. This study aimed to analyze the effects of KLF11 on H2O2-induced human brain VSMCs (HBVSMCs) in IA. We determined the mRNA levels of KLF11 in 15 paired arterial wall tissues of patients with IA and healthy volunteers. HBVSMCs were stimulated with H2O2 for 6 h to establish an IA model in vitro. Cell viability, apoptosis, and inflammatory cytokine (interleukin [IL-1ß, tumor necrosis factor-α, and IL-6) levels were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide, flow cytometry, and enzyme-linked immunosorbent assays, respectively. KLF11 expression was determined via quantitative reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence analyses. Furthermore, p-p38, p38, cleaved-caspase 3, and caspase 3 levels were determined via western blotting. KLF11 levels were downregulated in the arterial wall tissues of patients with IA than in those of the control group. KLF11 upregulation by KLF11-plasmid promoted the cell viability, reduced apoptosis, decreased cleaved-caspase 3 expression, and inhibited the secretion of inflammatory factors in H2O2-induced HBVSMCs. KLF11-plasmid remarkably reduced p-p38 expression and p-p38/p-38 ratio; however, these effects were reversed by P79350 treatment. Overall, KLF11 upregulation improved the HBVSMC functions and exerted protective effects against IA, suggesting its potential for IA treatment.

Repair of Asian nasal subunit defects using nasolabial perforator flaps: A retrospective study.

BACKGROUND: The application of nasolabial perforator flap for nasal reconstruction has been reported previously with satisfactory outcomes, but the outcomes and risk factors of postoperative adverse events have been unclear to plastic surgeons. AIMS: To statistically analyze the effectiveness of the nasolabial perforator flap in nasal reconstruction and the risk factor of postoperative complications and re-operation. PATIENTS/METHODS: This retrospective study evaluated 58 Chinese patients who underwent nasal reconstruction with the nasolabial perforator flap from 2009 to 2021. The esthetic and blood supply outcomes were measured by plastic surgeons on a 5-point Likert scale. Binary logistic regression was used to determine the risk factors associated with postoperative complications and re-operation. RESULTS: The mean age of the cohort was 66.4 ± 2.0 years. The defect size ranged from 6.5 × 5.5 mm2 to 40 × 70 mm2 , and 48.3% of defects covered more than one nasal subunit. Venous congestion occurred in 4.9% of flaps, and the immediate overall postoperative score was 7.72/10. More than one nasal subunit of involvement was the risk factor associated with re-operation (p = 0.004), but no risk factor was associated with complications. CONCLUSIONS: The nasolabial perforator flap is reliable for nasal reconstruction with good esthetic outcomes and fewer complications. However, a large number of involved subunits may lead to multiple surgeries for flap trimming in easterners.

hIMB1636-MMAE, a Novel TROP2-Targeting Antibody-Drug Conjugate Exerting Potent Antitumor Efficacy in Pancreatic Cancer.

Herein, we first prepared a novel anti-TROP2 antibody-drug conjugate (ADC) hIMB1636-MMAE using hIMB1636 antibody chemically coupled to monomethyl auristatin E (MMAE) via a Valine-Citrulline linker and then reported its characteristics and antitumor activity. With a DAR of 3.92, it binds specifically to both recombinant antigen (KD ∼ 0.687 nM) and cancer cells and could be internalized by target cells and selectively kill them with IC50 values at nanomolar/subnanomolar levels by inducing apoptosis and G2/M phase arrest. hIMB1636-MMAE also inhibited cell migration, induced ADCC effects, and had bystander effects. It displayed significant tumor-targeting ability and excellent tumor-suppressive effects in vivo, resulting in 5/8 tumor elimination at 12 mg/kg in the T3M4 xenograft model or complete tumor disappearance at 10 mg/kg in BxPc-3 xenografts in nude mice. Its half-life in mice was about 87 h. These data suggested that hIMB1636-MMAE was a promising candidate for the treatment of pancreatic cancer with TROP2 overexpression.

Elucidating the development, characterization, and antitumor potential of a novel humanized antibody against Trop2.

Trophoblast cell surface antigen 2 (Trop2) has emerged as a potential target for effective cancer therapy. In this study, we report a novel anti-Trop2 antibody IMB1636, developed using hybridoma technology. It exhibited high affinity and specificity (KD = 0.483 nM) in binding both antigens and cancer cells, as well as human tumor tissues. hIMB1636 could induce endocytosis, and enabled targeted delivery to the tumor site with an in vivo retention time of 264 h. The humanized antibody hIMB1636, acquired using CDR grafting, exhibited the potential to directly inhibit cancer cell proliferation and migration, and to induce ADCC effects. Moreover, hIMB1636 significantly inhibited the growth of MDA-MB-468 xenograft tumors in vivo. Mechanistically, hIMB1636 induced cell cycle arrest and apoptosis by regulating cyclin-related proteins and the caspase cascade. In comparison to commercialized sacituzumab, hIMB1636 recognized a conformational epitope instead of a linear one, bound to antigen and cancer cells with similar binding affinity, induced significantly more potent ADCC effects against cancer cells, and displayed superior antitumor activities both in vitro and in vivo. The data presented in this study highlights the potential of hIMB1636 as a carrier for the formulation of antibody-based conjugates, or as a promising candidate for anticancer therapy.

The Morphological and Functional Effects of the Endoscope-Assisted One-Stage Approach for Crooked Nose.

BACKGROUND: A crooked nose is an external nose deformity predominantly caused by congenital aplasia or acquired secondary to trauma or surgery, often accompanied by a deviated nasal septum. Patients with crooked nose have dual needs to improve both esthetic and functional problems. METHODS: The clinical and photographic information of 48 patients diagnosed with a crooked nose and nasal septum deviation treated from January 2018 to January 2022 was acquired. The morphology and functional effects were investigated by evaluating the general condition of the operation, measuring the esthetic indexes of the nose, and subjectively scoring. RESULTS: For both morphology and function, endoscopy-assisted one-stage correction showed positive results in this study. The external nose deviation distance postoperatively measured 1.28 (0.85, 1.97) mm, which significantly decreased from the preoperative value of 3.96 (3.31, 5.29) mm. The scores of doctors and irrelevant medical students on nose morphology increased significantly from 4.75±1.88 and 3.84±0.76 to 6.48±1.21 and 7.21±0.67, respectively. The rhinoplasty outcome evaluation score and the "nasal obstruction symptom evaluation "score of patients were both significantly improved ( t = -7.508 and t =6.310, respectively, P < 0.001). CONCLUSION: Endoscope-assisted one-stage correction of the crooked nose can restore nasal morphology, improve the symptoms of nasal obstruction, and achieve patient satisfaction. It is a minimally invasive, safe, effective, and fast recovery approach for patients who need to solve both esthetic and functional problems.

Full-endoscopic lumbar discectomy via lateral superior articular process approach for treating far lateral lumbar disc herniation: a retrospective study and technical note.

PURPOSE: This study aims to evaluate the efficacy and safety of the full-endoscopic lumbar discectomy (FELD) via lateral superior articular process (LSAP) approach and full-endoscopic transforaminal discectomy (FETD) for treating far lateral lumbar disk herniation (FFLDH). METHODS: From January 2020 to June 2022, patients who were diagnosed as FLLDH underwent the FELD via LSAP approach or FETD. The operation time, estimated blood loss, length of hospital stays, and complications were recorded. The visual analog scale (VAS) for back pain, VAS for leg pain, and the Oswestry Disability Index (ODI) scores was measured during preoperative and postoperative follow-up. RESULTS: Thirty-two patients were enrolled in this study, of which 12 patients were treated with the FELD via LSAP approach (LSAP-FELD group) and 20 patients underwent FETD (FETD group). The LSAP-FELD group exhibited significantly shorter operation times and hospital stays compared to the FETD group, while no statistically significant differences were observed in intraoperative blood loss and complication rates. There were no significant differences in the VAS for back pain, the VAS for leg pain, and the ODI score between the two groups preoperatively and three days, three months, and the last follow-up postoperatively. CONCLUSIONS: Both the FELD via LSAP approach and FETD have demonstrated favourable clinical efficacy in the treatment of FLLDH. Notably, the FELD via LSAP approach shows the advantages of shorter operation time and hospital stays.

Development and Validation of a Nomogram to Predict the Risk of Recurrent Lower Extremity Radiating Pain Within 1 Week Following Full-Endoscopic Lumbar Discectomy.

BACKGROUND: Accurately predicting the risk of lower extremity (LE) radiating pain after surgery is an important endeavor for spinal surgeons. Our study aimed to identify risk factors for LE radiating pain after decompression with full-endoscopic lumbar discectomy (FELD) and develop a nomogram. METHODS: We retrospectively reviewed the medical data of patients with lumbar disc herniation who underwent FELD. Two hundred thirty-five patients diagnosed at our hospital from January 2015 to December 2020 were used for model development. The independent risk factors for LE radiating pain after surgery were determined by least absolute shrinkage and selection operator logistic regression and multivariate logistic regression analysis. A nomogram was developed to predict the risk of LE radiating pain based on independent risk factors. Receiver operating characteristic curve, calibration curve, and decision curve analyses were used to evaluate the predictive performance. The nomogram was further verified by an independent cohort. RESULTS: Three hundred seventy-five patients were enrolled in this study, with 102 patients in the training cohort reporting LE radiating pain after FELD, while 133 patients did not. In the validation cohort, 57 patients reported LE radiating pain after FELD, while 83 patients did not. The model was established by multivariate logistic regression analysis. The risk factors included a higher Michigan State University classification of herniated discs, increased disease course, increased time of surgery, reduced lateral recess width, and an interlaminar surgical approach, compared to transforaminal approach. The C-indices and the area under the receiver operating characteristic curve of the predictive model demonstrated good discrimination. Good predictive performance and accuracy were also observed in the validation cohort. CONCLUSIONS: A novel nomogram for predicting recurrent LE radiating pain within 1 week after FELD was established and validated. More aggressive pain management strategies should be considered for patients at high risk of LE radiating pain after surgery, as predicted by this model.

Effect of laparoscopic pancreaticoduodenectomy on the incidence of surgical-site wound infection: A meta-analysis.

A meta-analysis was conducted to assess the impact of robotic and laparoscopic pancreaticoduodenectomies on postoperative surgical site wound infections. A comprehensive computerised search of databases, such as PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang Data, was performed to identify studies comparing robotic pancreaticoduodenectomy (PD) with laparoscopicPD. Relevant studies were searched from the inception of the database construction until April 2023. The meta-analysis outcomes were analysed using odds ratios (OR) with corresponding 95% confidence intervals (CI). The RevMan 5.4 software was used for the meta-analysis. The findings of the meta-analysis showed that patients who underwent laparoscopic PD had a significantly lower incidence of surgical-site wound (16.52% vs. 18.92%, OR: 0.78, 95% CI: 0.68-0.90, P = .0005), superficial wound (3.65% vs. 7.57%, OR: 0.51, 95% CI: 0.39-0.68, P < .001), and deep wound infections (1.09% vs. 2.23%, OR: 0.53, 95% CI: 0.34-0.85, P = .008) than those who received robotic PD. However, because of variations in sample size between studies, some studies suffered from methodological quality deficiencies. Therefore, further validation of this result is needed in future studies with higher quality and larger sample sizes.

A clinical nomogram for predicting the residual low back pain after percutaneous endoscopic surgery for lumbar disc herniation.

PURPOSE: Current findings suggest that minimally percutaneous endoscopic lumbar discectomy (PELD) is a practical therapeutic approach for lumbar disc herniation (LDH). However, some patients still end up with residual low back pain, even after surgery. Our study aims to construct and validate a nomogram to predict residual low back pain after PELD. METHODS: The medical records of 355 LDH patients admitted to the author's hospital were retrospectively analyzed between January 2019 and December 2021. The patients were randomly divided into two groups with a ratio of 7:3, namely a modelling group and a validation group. The univariable logistics and multivariable regression methods were used to screen the independent risk factors. A nomogram was then drawn using independent risk factors selected from the univariable and multivariable regression analyses. The concordance index (C-index), the receiver operating characteristic (ROC) curve, the calibration curve, and the decision curve analysis were used to evaluate the nomogram's performance. Finally, the accuracy of the nomogram was verified by a validation cohort. RESULTS: 36.6% (130/355) of patients showed low back pain after percutaneous endoscopic lumbar discectomy, while 63.4% (225/355) showed no symptoms. Multivariable logistical regression analysis showed that Modic change (p < 0.05, OR = 1.813), fatty infiltration of the paravertebral muscle (p < 0.05, OR = 2.935), and edema of lumbodorsal fascia (p = 0.049, OR = 1.611) were significant risk factors for post-operative residual back pain. Moreover, the C-index of the predictive nomogram was 0.743 (0.681-0.805), the area under the receiver operating characteristic curve (AUC) value was 0.739, and the DCA results exhibit a net benefit between 0.16 and 0.66. The above internal validation methods demonstrate the nomogram's good predictive capability. CONCLUSION: Each variable in the model had a quantitatively corresponding risk score, which can be used in predicting residual low back pain after PELD.

Antitumor efficacy of a recombinant EGFR-targeted fusion protein conjugate that induces telomere shortening and telomerase downregulation.

OBJECTIVE: To prepare a recombinant EGFR-targeted fusion protein drug conjugate acting on telomere and telomerase; and evaluate its antitumor efficacy. METHODS: We prepared a recombinant fusion protein Fv-LDP-D3 which consists of the Fv fragment of an anti-EGFR monoclonal antibody (MAb), the apoprotein of lidamycin (LDP), and the third domain (D3) of human serum albumin (HSA); then generated the conjugate Fv-LDP-D3∼AE by integrating the active enediyne chomophore (AE) of lidamycin. Accordingly, in vitro and in vivo experiments were performed. RESULTS: As shown, Fv-LDP-D3 specifically bound to EGFR highly-expressing cancer cells and intensely entered K-Ras mutant cells via enhanced macropinocytosis. By in vivo imaging, Fv-LDP-D3 displayed intense accumulation and persistent retention in tumor-site. Furthermore, the conjugate Fv-LDP-D3∼AE displayed highly potent cytotoxicity to cancer cells with IC50 at 0.1 nM level. The conjugate induced telomere shortening and downregulation of telomerase and EGFR pathway related proteins. Fv-LDP-D3∼AE exhibited prominent antitumor efficacy against human colorectal cancer xenograft accompanying with significant increase of serum IFN-ß in athymic mice. CONCLUSION: The recombinant fusion protein conjugate that exhibits the capability of tumor-targeting drug delivery can induce telomere shortening and telomerase downregulation. The investigation may lay the foundation for the development of MAb-HSA domain-based fusion protein drug conjugates.

Impact of local steroid application on dysphagia after anterior cervical spine surgery: a meta-analysis.

INTRODUCTION: Dysphagia is one of the most common complications of anterior cervical spine surgery. Local steroid was widely used to reduce the postoperative swallowing pain. However, the effect of local steroid application on dysphagia after anterior cervical spine surgery was still uncertain. MATERIALS AND METHODS: We searched Medline (PubMed), Embase and the Cochrane Library on July 27, 2021 for studies investigating the effect of local steroid application on dysphagia after anterior cervical spine surgery from their date of inception to 2021. The relative risk or weighted mean difference with 95% confidence interval was recorded as a summary statistic consist of postoperative dysphagia, swallowing VAS scores, SWAL-QOL scores, PSTSI, and steroid related complications. RESULTS: This meta-analysis included 7 RCT studies involving 254 patients in the steroid group and 232 patients in the placebo group. Results showed local steroid group had less patients with dysphagia, lower swallowing VAS scores and less severe of prevertebral soft-tissue edema on the fourth day after surgery. No significant difference in non-fusion rate between the two groups was observed. And all included studies had no serious steroid related complications reported. CONCLUSIONS: The use of local steroid in anterior cervical spine surgery could reduce the early postoperative dysphagia without serious steroid related complication. However, the safety of local steroid application still need further studies with larger samples.

Inhibited transcription factor EB function induces reactive oxygen species overproduction to promote pyroptosis in cadmium-exposed renal tubular epithelial cells.

Pyroptosis is a pro-inflammatory type of cell death involved in the pathogenesis of multiple kidney diseases, while transcription factor EB (TFEB) is shown to be important for rescuing renal function. Cadmium (Cd) is an omnipresent toxic heavy metal with definite nephrotoxicity, but there is lacking of evidence regarding an interplay between TFEB activity and pyroptosis during Cd exposure. In this study, Cd-exposed NRK-52E cells were used to clarify this issue as an in vitro model of acute kidney injury. First, our results showed that Cd exposure evidently elevated the protein levels involved in pyroptosis, increased lactate dehydrogenase (LDH) release, and disrupted the cell membrane integrity, suggesting the occurrence of pyroptosis in NRK-52E cells. It is also shown that Cd induced a burst of reactive oxygen species (ROS) to mediate pyroptosis. Simultaneously, downregulated TFEB expression with its inhibited nuclear translocation was revealed in Cd-exposed NRK-52E cells. Further investigations have demonstrated that TFEB knockdown promoted Cd-induced ROS production to exacerbate the pyroptosis, while TFEB overexpression inhibited Cd-induced ROS production to alleviate the pyroptosis in NRK-52E cells. In summary, these findings demonstrate that Cd-inhibited TFEB function results in ROS overproduction to promote pyroptosis in NRK-52E cells, which provide new insight into the therapeutic targets for Cd-induced kidney diseases.

Deep Learning Promotes the Screening of Natural Products with Potential Microtubule Inhibition Activity.

Natural microtubule inhibitors, such as paclitaxel and ixabepilone, are key sources of novel medications, which have a considerable influence on anti-tumor chemotherapy. Natural product chemists have been encouraged to create novel methodologies for screening the new generation of microtubule inhibitors from the enormous natural product library. There have been major advancements in the use of artificial intelligence in medication discovery recently. Deep learning algorithms, in particular, have shown promise in terms of swiftly screening effective leads from huge compound libraries and producing novel compounds with desirable features. We used a deep neural network to search for potent ß-microtubule inhibitors in natural goods. Eleutherobin, bruceine D (BD), and phorbol 12-myristate 13-acetate (PMA) are three highly effective natural compounds that have been found as ß-microtubule inhibitors. In conclusion, this paper describes the use of deep learning to screen for effective ß-microtubule inhibitors. This research also demonstrates the promising possibility of employing deep learning to develop drugs from natural products for a wider range of disorders.

Comparison of Postoperative Outcomes Between Percutaneous Endoscopic Lumbar Interbody Fusion and Minimally Invasive Transforaminal Lumbar Interbody Fusion for Lumbar Spinal Stenosis.

Objective: This study aimed to compare postoperative outcomes in surgical and patient-reported outcomes (PROs) between percutaneous endoscopic lumbar interbody fusion (PE-LIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) for the treatment of lumbar spinal stenosis (LSS). Methods: We reviewed a total of 89 patients undergoing single-level surgery for lumbar spinal stenosis from January 2018 to July 2021. The cases were categorized as PE-LIF (Group PE-LIF, 41 cases) or MIS-TLIF (Group MIS-TLIF, 48 cases) approach. Parameters obtained at baseline through at least six months of follow-up were collected. The surgical outcomes involving the operative time, estimated blood loss, postoperative bed staying time, and length of hospital stays were analyzed. PROs included the Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), modified MacNab standard evaluation, intervertebral fusion rate, and postoperative complications. Results: A total of 89 patients were included in this analysis involving 41 patients who underwent PE-LIF and 48 patients who underwent MIS-TLIF. The 2 groups were similar in gender, age, body mass index, follow-up time and surgery levels (P > 0.05), and were not significantly different in the length of hospital stays (P > 0.05). PE-LIF had a significantly longer operative time, greater fluoroscopy time, lower estimated blood loss and shorter bed rest time than MIS-TLIF. Both groups improved significantly from baseline for the VAS and ODI scores. PE-LIF was associated with a lower VAS score for back pain at three-day after surgery. There were no significant differences between PE-LIF and MIS-TLIF in the excellent or good rates and intervertebral fusion rates at the last follow-up (P > 0.05). As for related complications, there were no significant complications occurred, and no significant differences were seen in the complications between both groups (P > 0.05). Conclusions: To summarize, PE-LIF and MIS-TLIF are both safe and effective for LSS. PE-LIF has a definite short-term curative effect with less trauma.

HIF-1α upregulation exerts the antagonistic effect against angiogenesis inhibition in manganese deficiency-induced tibial dyschondroplasia of broiler chicks.

Manganese (Mn) is an essential microelement for broiler breeding and its deficiency causes tibial dyschondroplasia (TD). Tibial growth plate (TGP) development and metaphyseal vascularization are crucial for tibia growth in fast-growing broiler chickens, but their roles in Mn deficiency-induced TD in chicks remain unclear. This study was designed to clarify this issue. A total of 36 one-day-old broilers were divided into the control group and Mn-deficiency (Mn-D) group, which were fed with a standard diet (60 mg Mn/kg) and Mn deficiency diet (22 mg Mn/kg) for 42 days, respectively. TGP and proximal tibial metaphysis were collected to perform the related assays. This study found that Mn deficiency decreased the tibia length and TGP thickness in the TD model. Also, Mn deficiency increased the irregular and white tibial dyschondroplasia lesions (TDL) region under the TGP, and reduced the expression levels of vascular endothelial growth factor (VEGF) and macrophage migration inhibitory factor (MIF). Combined with histological assessment, it was suggested that Manganese deficiency inhibited angiogenesis in the proximal tibial metaphysis. Meanwhile, Mn deficiency enhanced the expression levels of hypoxia-inducible factor-1 α (HIF-1α), autophagy-related protein 5 (ATG5), and microtubule-associated protein 1 light chain 3 ß (LC3-II) in TGP, but decreased the expression level of SQSTM1 (P62), which suggested that autophagy was activated during this process. Collectively, these data indicate that HIF-1α up-regulation and concurrent autophagy activation exert a protective effect against Mn deficiency-induced angiogenesis inhibition, which may provide useful guidance to prevent TD in broilers.