Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options.

Drug resistance represents a significant obstacle in cancer treatment, underscoring the need for the discovery of novel therapeutic targets. Ubiquitin-specific proteases (USPs), a subclass of deubiquitinating enzymes, play a pivotal role in protein deubiquitination. As scientific research advances, USPs have been recognized as key regulators of drug resistance across a spectrum of treatment modalities, including chemotherapy, targeted therapy, immunotherapy, and radiotherapy. This comprehensive review examines the complex relationship between USPs and drug resistance mechanisms, focusing on specific treatment strategies and highlighting the influence of USPs on DNA damage repair, apoptosis, characteristics of cancer stem cells, immune evasion, and other crucial biological functions. Additionally, the review highlights the potential clinical significance of USP inhibitors as a means to counter drug resistance in cancer treatment. By inhibiting particular USP, cancer cells can become more susceptible to a variety of anti-cancer drugs. The integration of USP inhibitors with current anti-cancer therapies offers a promising strategy to circumvent drug resistance. Therefore, this review emphasizes the importance of USPs as viable therapeutic targets and offers insight into fruitful directions for future research and drug development. Targeting USPs presents an effective method to combat drug resistance across various cancer types, leading to enhanced treatment strategies and better patient outcomes.

Application of OFA-based ERAS for video-assisted thoracoscopic surgery in elderly patients with airway stenosis: A case report.

BACKGROUND: Thoracic surgery without general anesthesia can be traced back to the First World War, and thoracic epidural block was used to complete the operation due to a large number of patients with gunshot wounds who needed emergency thoracic surgery. By reducing the intraoperative opioid dose, intraoperative and postoperative opioid-related adverse events such as respiratory depression, nausea and vomiting, delirium, hyperalgesia, and other side effects can be reduced to the benefit of patients. METHODS: A 72-year-old male patient was admitted to the hospital with a 5-day history of multifocal pain throughout the body caused by a fall. The injury was not treated at that time, and the pain gradually increased, accompanied by cough with difficulty expelling sputum. DIAGNOSES: Left lung contusion; traumatic pneumonia; multiple left rib fractures; left fluid pneumothorax; thyroid tumor of unknown nature, possibly malignant. Grade I tracheal stenosis; Sequelae of cerebral infarction. Because of goiter and severe tracheal compression, the patient was not intubated and received deopiated general anesthesia combined with epidural anesthesia to preserve spontaneous breathing. OUTCOMES: At the end of the video-assisted thoracoscopic exploration, the patient was immediately conscious and returned directly to the ward 6 min later. The patient was able to move freely after surgery and eat normally within 6 h of surgery. The postoperative visual analog scale score was 2 points, and there were no anesthetic complications during the follow-up. CONCLUSION: The opioid-free anesthesia strategy of tubeless general anesthesia, allowing spontaneous breathing combined with epidural anesthesia in elderly patients with tracheal stenosis undergoing video-assisted thoracoscopic surgery can not only avoid accidents and injuries caused by tracheal intubation and mechanical ventilation, but can also significantly reduce postoperative respiratory complications, optimize postoperative analgesia, and help achieve enhanced recovery after surgery.

Opioid-free anesthesia with ultrasound-guided quadratus lumborum block in the supine position for lower abdominal or pelvic surgery: a randomized controlled trial.

In the past, quadratus lumborum block (QLB) was mostly used for postoperative analgesia in patients, and few anesthesiologists applied it during surgery with opioid-free anesthesia (OFA). Consequently, it is still unclear whether QLB in the supine position can provide perfect analgesia and inhibit anesthetic stress during surgery under the OFA strategy. To observe the clinical efficacy of ultrasound-guided quadratus lumborum block (US-QLB) in the supine position with OFA for lower abdominal and pelvic surgery. A total of 122 patients who underwent lower abdominal or pelvic surgery in People's Hospital of Wanning between March 2021 and July 2022 were selected and divided into a quadratus lumborum block group (Q) (n = 62) and control group (C) (n = 60) according to the random number table method. Both groups underwent general anesthesia combined with QLB in the supine position. After sedation, unilateral or bilateral QLB was performed via the ultrasound guided anterior approach based on images resembling a "human eye" and "baby in a cradle" under local anesthesia according to the needs of the operative field. In group Q, 20 ml of 0.50% lidocaine and 0.20% ropivacaine diluted in normal saline (NS) were injected into each side. In group C, 20 ml of NS was injected into each side. The values of BP, HR, SPO2, SE, RE, SPI, NRS, Steward score, dosage of propofol, dexmedetomidine, and rocuronium, the number of patients who needed remifentanil, propofol, or diltiazem, puncture point, block plane, duration of anesthesia, catheter extraction, and wakefulness during the operation were monitored. There were no significant differences in the general data, number of cases requiring additional remifentanil, propofol, or diltiazem treatment, as well as puncture point and puncture plane between the two groups (P > 0.05). HR, SBP, and DBP values were higher in group Q than in group C at T1; HR, SPI, and SE, while RE values were lower in group Q than in group C at T3, SE, and RE; the Steward score was higher in group Q than in group C at T4 and T5, and the difference was statistically significant (P < 0.05). The extubation and awake times were lower in group Q than in group C, and the difference was statistically significant (P < 0.05). The SE, RE, and SPI values were lower at T1, T2, T3, and T4 than at T0. The Steward scores at T4 and T5 were higher in group Q than in group C, and were lower than at T0, with a statistically significant difference (P < 0.05). There were significant differences in the effectiveness of postoperative analgesia between the two groups at t1, t3 and t4 (P < 0.05). US-QLB in the supine position with OFA is effective in patients undergoing lower abdominal or pelvic surgery with stable intraoperative vital signs, complete recovery and better postoperative analgesia.

The effects of ultrasound-guided QLB and TAPB combined with opioid-free anesthesia (OFA) on clinical efficacy of the patients undergoing abdominal surgery.

Background: Although opioids provide effective analgesia for abdominal surgery, they also present serious unwanted side effects. Ultrasound-guild quadratus lumborum block (QLB) and transversus abdominis plane block (TAPB) have been proven to offer long-lasting and efficient analgesia during abdominal surgery. However, the clinical efficacy of ultrasound-guided QLB and TAPB combined with opioid-free anesthesia (OFA) in abdominal surgery remains unclear. Objective: This study aimed to investigate the impact of ultrasound-guided QLB and TAPB combined with opioid-free anesthesia (OFA) on the clinical efficacy of abdominal surgery. Methods: A total of 122 patients scheduled for abdominal surgery at People's Hospital of Wanning between March 2021 and April 2022 were enrolled in this study. Participants were randomly divided into two groups: the experimental group (QLB/TAPB + OFA, 62 patients) and the control group (opioid anesthesia, 60 patients). The clinical efficacy of the QLB/TAPB combined with OFA technique was evaluated by analyzing patients' vital signs, postoperative consciousness recovery time, numeric rating scale (NRS) score, and immune function in both groups. Results: We observed that systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) in experimental group were significantly higher than those in control group after induction (p < 0.05). Heart rate (HR) in experimental group was significantly lower than in the control group at intraoperative 1h (p < 0.05). Additionally, bispectral index (BIS), state entropy (SE), and response entropy (RE) levels in the experimental group were significantly higher than those in the control group (p < 0.05). Furthermore, extubation and awakening time were significantly shorter in the experimental group compared to the control group (p < 0.05). The NRS scores in the experimental group were markedly lower than those in the control group. Moreover, IL-6 and CRP levels in the experimental group were obviously lower than in the control group after postoperative 1d (p < 0.05). Interestingly, IL-6 (p < 0.001), CRP (p < 0.001), and PCT (p = 0.037) levels in female patients of the experimental group were all significantly lower than those in the control group after postoperative 1d. Conclusions: Ultrasound-guided QLB and TAPB combined with OFA technique can reduce pain intensity and enhance the patients' immune function in abdominal surgery.

Application of surgical pleth index in the opioid-free anesthesia: A randomized controlled trial.

BACKGROUND: Currently, there is no gold standard for monitoring noxious stimulation during surgery, and the surgical pleth index (SPI) is only one of many monitoring methods. It is commonly used in the monitoring of conventional opiate anesthesia, but its effectiveness in opioid-free anesthesia (OFA) has not been evaluated. Therefore, the aim of this study was to observe the guidance value of the surgical pleth index in opioid-free anesthesia for patients undergoing lower abdominal or pelvic surgery. METHODS: A total of 122 patients who underwent lower abdominal or pelvic surgery in our hospital between March 2021 and July 2022 were selected and equally divided into OFA (F) and control (C) groups according to the random number table method. Both groups underwent ultrasound-guided unilateral/bilateral quadratus lumborum block in the supine position according to the surgical field. In group F, 0.50% lidocaine and 0.20% ropivacaine (in 20 mL of 0.9% normal saline) were injected on each side. In group C, 20 mL 0.9% normal saline was injected on each side. Group F received general anesthesia without opioids and group C received general anesthesia with opioids. BP, pulse oxygen saturation, PETCO2, reactionentropy, stateentropy, and SPI values; Steward score; dosage of propofol, dexmedetomidine, rocuronium, and diltiazem; extubation time; and awake time were monitored in both groups. RESULTS: There were no significant differences in the general data between the 2 groups (P > .05). There were no significant differences in SPI values at T0, T1, T2, T3, T4, and T5 or the number of cases requiring additional remifentanil, propofol, and diltiazem between the 2 groups (P > .05). The stateentropy, reactionentropy, and Steward scores were higher in group F than in group C at T4 and T5, while the extubation and awake times were lower in group F than in group C (P < .05). The heart rate and SPI of group F were lower than that of group C at T3 (P < .05). CONCLUSION: The guiding value of SPI in OFA was similar to its use in opiated anesthesia. Its clinical efficacy is exact, vital signs are stable, enabling rapid, and complete regaining of consciousness.

Effect of esketamine on inflammatory factors in opioid-free anesthesia based on quadratus lumborum block: A randomized trial.

BACKGROUND: As strong analgesics, opioids provide the analgesic component of general anesthesia, but they have bidirectional effects on the immune system, promoting the production of pro-inflammatory factors. The idea of opioid-free anesthesia is to replace the analgesic effect of opioids in the treatment of acute pain with comparably effective drugs that do not affect the immune system and thereby decrease the production of inflammatory factors. Therefore, this study aims to observe the effect of opioid-free esketamine anesthesia based on quadratus lumborum block on inflammatory factors in patients undergoing lower abdominal or pelvic surgery. METHODS: A total of 122 patients who underwent lower abdominal or pelvic surgery in our hospital from March 2021 to June 2022 were selected and divided into the esketamine (E) group (n = 62) and control (C) group (n = 60) according to the random number table method. According to the surgical field, the 2 groups underwent unilateral/bilateral quadratus lumborum block in the supine position under ultrasound guidance. In addition, both groups received a target controlled infusion of propofol 3 to 3.5 µg/mL and intravenous rocuronium 0.8 mg/kg. Group E was given opioid-free anesthesia, group C was given opioid-based anesthesia. A 3 to 5 laryngeal mask was inserted according to body weight, and rocuronium 0.5 mg/kg was added intermittently. The levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), procalcitonin, tumor necrosis factor-α (TNF-α), numeric rating scales, dosage of propofol, dexmedetomidine and rocuronium, as well as the numeric rating scales score and analgesic complications were monitored in the 2 groups. RESULTS: There was no significant differences in general outcomes between the 2 groups (P > .05). The blood pressure in group E was higher than in group C at T1 (P < .05). The levels of IL-6, TNF-α, CRP and IL-8 in group E were significantly lower than in group C at T1, T2, T3, and T4 (P < .05). The levels of IL-6, TNF-α, procalcitonin, CRP and IL-8 in the 2 groups at T1, T2, T3, and T4 were significantly higher than at T0 (P < .05). CONCLUSION: Opioid-free esketamine anesthesia based on quadratus lumborum block achieved perfect postoperative analgesia with little effect on inflammatory factors in patients undergoing lower abdominal or pelvic surgery.

RNF167-mediated ubiquitination of Tollip inhibits TNF-α-triggered NF-κB and MAPK activation.

Toll-interacting protein (Tollip) is a multifunctional regulator in cellular activities. However, whether its functions are subjected to post-translational modifications remains elusive. Here, we identified ubiquitination as a post-translational modification on Tollip. We found that Tollip interacted with ring finger protein 167 (RNF167) through its C-terminal coupling of ubiquitin to ER degradation (CUE) domain, and RNF167 functioned as the potential E3 ligase to attach K33-linked poly-ubiquitin chains to the Lys235 (K235) site of Tollip. Furthermore, we discovered Tollip could inhibit TNF-α-induced nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation, and substitution of Lys235 on Tollip to arginine failed to suppress TNF-α-NF-κB/MAPK (JNK) cascades, revealing the role of Tollip and its ubiquitination in NF-κB/MAPK pathways. Thus, our study reveals the novel biological function of Tollip and RNF167-dependent ubiquitination of Tollip in TNF-α signaling.

Application of an OFA strategy to ERAS in a 102-year-old patient undergoing colon cancer surgery: A case report.

RATIONALE: Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Opioid-free anesthesia (OFA) is an opioid-sparing technique that focuses on multimodal or balanced analgesia, relying on non-opioid adjuncts and regional anesthesia. Enhanced recovery after surgery (ERAS) protocols, often under the auspices of a perioperative pain service, can help guide and promote opioid reduced and OFA, without negatively impacting perioperative pain management or recovery. Ultrasound-guided regional nerve block is currently a good option for OFA due to anesthesiologists' mastery of ultrasound techniques. The safety of the OFA strategy for quadratus lumborum block (QLB) + transversus abdominis plane block (TAP) in the super-elderly patients has not been reported and remains unclear. We report a case of OFA anesthesia in a super-elderly patient with colon cancer. PATIENT CONCERNS: A 102-year-old female was admitted to the hospital due to "abdominal pain for a week" and received conservative treatment for more than 20 days, with poor results. DIAGNOSES: The patient was diagnosed with colorectal cancer associated with bronchiectasis and infection, multiple nodules in the right lower lung, and sinus arrhythmia. INTERVENTIONS: As the patient was a super-elderly patient with multiple diseases, we used an OFA strategy with general anesthesia combined with QLB and TAP. OUTCOMES: The patient awakened quickly and completely after surgery, and extubation was successful 2 min after surgery without anesthesia complications, which is in line with the concept of ERAS. LESSONS: The OFA strategies of ultrasound guidance quadratus lumborum block (Ul-QLB) and ultrasound guidance transversus abdominis plane block (Ul-TAP) may be safe and effective for ERAS in super-elderly patients with colorectal cancer surgery.

HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer.

HtrA serine peptidase 3 (HTRA3) participates in multiple signal pathways and plays an important regulatory role in various malignancies; however, its role on prognosis and immune infiltrates in gastric cancer (GC) remains unclear. The study investigated HTRA3 expression in tumor tissues and its association with immune infiltrates, and determined its prognostic roles in GC patients. Patients with GC were collected from the cancer genome atlas (TCGA). We compared the expression of HTRA3 in GC and normal gastric mucosa tissues with Wilcoxon rank sum test. And logistic regression was used to evaluate the relationship between HTRA3 and clinicopathological characters. Gene ontology (GO) term analysis, Gene set enrichment analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) was conducted to explain the enrichmental pathways and functions and quantify the extent of immune cells infiltration for HTRA3. Kaplan-Meier analysis and Cox regression were performed to evaluate the correlation between HTRA3 and survival rates. A nomogram, based on Cox multivariate analysis, was used to predict the impact of HTRA3 on prognosis. High HTRA3 expression was significantly correlated with tumor histological type, histological grade, clinical stage, T stage, and TP53 status (P < 0.05). HTRA3-high GC patients had a lower 10-year progression-free interval [PFI; hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02-2.08; P = 0.038], disease-specific survival (DSS; HR: 1.65; CI: 1.08-2.52; P = 0.021) and overall survival (OS; HR: 1.59; CI: 1.14-2.22; P = 0.006). Multivariate survival analysis showed that HTRA3 was an independent prognostic marker for PFI (HR: 1.456; CI: 1.021-2.078; P = 0.038), DSS (HR: 1.650; CI: 1.079-2.522; P = 0.021) and OS [hazard ratio (HR): 1.590; 95% confidence interval (CI):1.140-2.219; P = 0.006]. The C-indexes and calibration plots of the nomogram based on multivariate analysis indicated an effective predictive performance for GC patients. GSEA showed that High HTRA3 expression may activate NF-κB pathway, YAP1/WWTR1/TAZ pathway, and TGFß pathway. There was a negative correlation between the HTRA3 expression and the abundances of adaptive immunocytes (T helper cell 17 cells) and a positive correlation with abundances of innate immunocytes (natural killer cells, macrophages etc.). HTRA3 plays a vital role in GC progression and prognosis and could be a moderate biomarker for prediction for survival after gastrectomy.

Cathepsin F Knockdown Induces Proliferation and Inhibits Apoptosis in Gastric Cancer Cells.

Gastric cancer (GC) is one of the most common cancers in the world. The cathepsin F (CTSF) gene has recently been found to participate in the progression of several types of cancer. However, the clinical characteristics and function of CTSF in GC as well as its molecular mechanisms are not clear. Six GC cell lines and 44 paired adjacent noncancerous and GC tissue samples were used to assess CTSF expression by quantitative polymerase chain reaction (qPCR). We used lentivirus-mediated small hairpin RNA (Lenti-shRNA) against CTSF to knock down the expression of CTSF in GC cells. Western blot and qPCR were used to analyze the mRNA and related protein expression. The biological phenotypes of gastric cells were examined by cell proliferation and apoptosis assays. Microarray-based mRNA expression profile screening was also performed to evaluate the potential molecular pathways in which CTSF may be involved. The CTSF mRNA level was associated with tumor differentiation, depth of tumor invasion, and lymph node metastasis. Downregulation of CTSF expression efficiently inhibited apoptosis and promoted the proliferation of GC cells. Moreover, a total of 1,117 upregulated mRNAs and 1,143 downregulated mRNAs were identified as differentially expressed genes (DEGs). Further analysis identified the involvement of these mRNAs in cancer-related pathways and various other biological processes. Nine DEGs in cancer-related pathways and three downstream genes in the apoptosis pathway were validated by Western blot, which was mainly in agreement with the microarray data. To our knowledge, this is the first report investigating the effect of CTSF on the growth and apoptosis in GC cells and its clinical significance. The CTSF gene may function as a tumor suppressor in GC and may be a potential therapeutic target in the treatment of GC.

Direct Observation of Ordered High-Spin-Low-Spin Intermediate States of an Iron(III) Three-Step Spin-Crossover Complex.

A neutral mononuclear Fe(III) complex [Fe(III) (H-5-Br-thsa-Me)(5-Br-thsa-Me)]⋅H2 O (1; H2 -5-Br-thsa-Me=5-bromosalicylaldehyde methylthiosemicarbazone) was prepared that exhibited a three-step spin-crossover (SCO) with symmetry breaking and a 14 K hysteresis loop owing to strong cooperativity. Two ordered intermediate states of 1 were observed, 4HS-2LS and 2HS-4LS, which exhibited reentrant phase-transition behavior. This study provides a new platform for examining multistability in SCO complexes.

Bis-(thio-cyanato-κN)[tris(pyridin-2-yl-meth-yl)amine-κ(4) N]-iron(II).

In the title complex, [Fe(NCS)2(C18H18N4)], the Fe(II) cation is chelated by a tris-(2-pyridyl-meth-yl)amine ligand and coordin-ated by two thio-cyanate anions in a distorted N6 octa-hedral geometry. In the crystal, weak C-H⋯S hydrogen bonds and π-π stacking inter-actions between parallel pyridine rings of adjacent mol-ecules [centroid-centroid distance = 3.653 (3) Å] link the mol-ecules into a two-dimensional supra-molecular architecture. The structure contains voids of 124 (9) Å(3), which are free of solvent molecules.