Pancreatic β-cells fine-tune glucose homeostasis through insulin secretion. The endoplasmic reticulum (ER) is critical for insulin production, relying on the unfolded protein response (UPR) to adapt to the body's fluctuating demands. Islets from both type 1 (T1D) and type 2 diabetes (T2D) exhibit inflammation, β-cell dysfunction, and loss. ER stress is present in the inflamed islets of autoimmune diabetes-prone mice and individuals with T1D and T2D. Inflammatory cytokines induce ER stress and disrupt UPR regulation, driving β-cell apoptosis and contributing to diabetes development. Inflammatory cytokines, e.g., IL-1β, impair β-cell function and survival, contributing to diabetes pathogenesis by inducing stress, altering gene expression, driving dedifferentiation, and reducing insulin production. Paradoxically, β-cells exhibit a high density of IL-1R1, and IL-1R1/KO mice display impaired glucose tolerance and reduced insulin secretion. Postprandial IL-1β secreted by macrophages helps maintain blood glucose homeostasis. These observations suggest that circulating low IL-1β concentrations may have physiologically relevant roles; however, their effects on β-cell function and survival remain unclear due to conflicting reports. Preconditioning β-cells with physiological circulating levels of IL-1β (IL-1β^low) induced a resilient state, protecting them from pro-inflammatory cytokine (CYT)-induced cell death while preserving glucose-stimulated insulin secretion through hormesis. IL-1β^low-treated INS-1E cells reduced CYT-induced NO secretion by suppressing NF-κB signaling and decreasing iNOS expression, correlating with reduced β-cell death. IL-1β^low conditioning reduced ER stress and upregulated p-eIF2α in response to CYT, thereby enhancing the expression of ER chaperones and biomarkers linked to improved β-cell identity/functionality. Transcriptomic analysis revealed that IL-1β^low preconditioning mitigated the CYT-induced loss of genes involved in β-cell function/identity, and suppressed the expression of genes linked to NF-κB signaling, cytokine-induced inflammation, and apoptosis. IL-1β^low treatment counteracted the upregulation of stress-related genes triggered by pro-inflammatory stimuli. Enhancing IL-1β^low-induced stress-response hormesis may provide a novel strategy to sustain β-cell function and survival during harmful diabetic inflammation.

The lipid-activated novel protein kinase C isoform, PKCε, plays a key role in the progression of Type 2 Diabetes Mellitus (T2DM) and has also been implicated in cancer, cardiac hypertrophy, pain and anxiety. As the spatial regulation of PKCε activity is linked to its interaction with the Receptor for Activated C Kinase 2 (RACK2, also known as COPB2), blockade of this interaction has potential therapeutic benefits for the treatment of several pathologies. Using a proximity-based chemiluminescent assay to monitor the binding of lipid-activated PKCε to RACK2, we discovered inhibitory peptides derived from the PKCε sequence; pentapeptides with a KxKxx motif and a C-terminal carboxylate potently inhibited this interaction, whereas other short sequences containing cationic residues were less effective. An alanine scan of the KIKIC peptide showed that the two Lys residues and C-terminal carboxylate were the most important for inhibitory activity. A previously described PKCε translocation inhibitory peptide from PKCε, εV1-2, exhibited much weaker inhibition of the PKCe-RACK2 interaction, with significant inhibitory activity observed only when it was conjugated to cell-penetrating peptides. KIKIC exhibited moderate cell-penetrating ability, showed no evidence of cytotoxicity, and modified PKCε translocation in response to lipid treatment. Several proteins that were captured in a RACK2 pulldown of a liver lysate in a KIKIC-peptide sensitive manner were identified as part of a PKCε-RACK2 complex isolated from intact cells. These results provide a basis for the rational design of peptides or peptidomimetics that inhibit the PKCε-RACK2 interaction and have potential for the prevention and/or treatment of T2DM.

Podocyte injury significantly contributes to glomerular filtration dysfunction and albuminuria in diabetic nephropathy (DN). Circular RNAs, particularly circFAT1 (hsa_circ_0001461), have emerged as influential regulators in pathological processes. This research focused on exploring the function of hsa_circ_0001461 in high glucose (HG)-induced podocyte damage and the associated underlying mechanism. Here, we demonstrate that circFAT1 is significantly upregulated in HPCs under HG conditions. Inhibition of circFAT1 led to decreased podocyte migration and a restoration of differentiation markers, along with a reduction in mesenchymal markers. Mechanistically, circFAT1 was found to inhibit miR-30e-5p, resulting in enhanced SOX4 expression, which promoted epithelial-mesenchymal transition and migration in podocytes. Moreover, we identified EIF4A3 as a crucial regulator of circFAT1 biogenesis under hyperglycaemic conditions. Importantly, elevated levels of circFAT1 were also detected in DN patients, correlating with increased albuminuria and serum creatinine. In conclusion, this study elucidates the critical role of circFAT1 in HG-induced podocyte injury through the miR-30e-5p/SOX4 signalling pathway. The findings suggest that targeting circFAT1 May offer a potential strategy for DN intervention.

To evaluate the accuracy of fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) in detecting metastatic uveal melanoma (UM) using both per-patient and per-lesion analyses, while also characterizing lesion detectability across various metastatic sites.

In this retrospective study conducted from January 2011 to September 2024, UM participants underwent PET/CT scans for follow-up or suspected recurrence. The lesion uptake were quantified by maximum standardized uptake value (SUVmax). Pathology and clinical follow-up served as reference standard.

Fifty-five participants (mean age, 49.2 ± 12.7; 26 females) were evaluated, and the average recurrent time was 30.7 months (IQR, 18.0-89.2). On per-patient level, 31 patients (56%) were confirmed to have metastatic lesions through pathology or clinical follow-up, of which 28/31 (90.3%) patients were successfully detected by ¹⁸F-FDG PET/CT and 3/31 (9.7%) patients with liver metastases were missed. Seventeen of 31 patients (54.8%) had multiple organ involvement. On per-lesion level, a total of 270 lesions were comfirmed, of which 245 (90.7%) were detected by ¹⁸F-FDG PET/CT, including metastasis to liver (103 of 128, 80.5%), bone (64 of 64, 100%), lymph node (24 of 24, 100%), lung (33 of 33, 100%), and other uncommen sites (21 of 21, 100%). The detection ability of ¹⁸F-FDG for liver metastases was positively correlated with the diameter of the lesions (r² = 0.671, p = 0.000). ¹⁸F-FDG successfully detected all bone, lymph node, and lung metastases, with 30 of 64 (46.9%) bone metastases showing no changes on CT and 12 of 24 (50%) lymph node metastases being less than 10 mm, making them prone to misdiagnosis on CT.

¹⁸F-FDG PET/CT may be a useful diagnostic tool in detecting metastatic UM, especially for early bone metastases and small lymph nodes. Added contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) may be still needed for tiny liver metastases detection.

Surgical treatment of parapharyngeal space tumors using traditional methods is associated with a high risk of significant complications, and conventional open surgery has limitations in terms of visualization. This study aims to compare the safety and efficacy of transoral endoscopic surgery combined with the Electromagnetic Navigation system (TOES + ENS) with traditional surgical methods (translateral approach and TOES without ENS) in the treatment of parapharyngeal space tumors.

We conducted a retrospective comparative analysis of 41 patients diagnosed with parapharyngeal space tumors who underwent surgical resection. Patients were divided into two groups: the TOES + ENS group (T group, n = 21) and the traditional surgery group (C group, n = 20). Primary outcome measures included surgical duration, intraoperative blood loss, postoperative visual analog scale (VAS) pain scores, time to first oral intake, length of hospital stay, and the incidence and severity of postoperative complications, the latter classified using the Clavien-Dindo system.

Both groups achieved high tumor resection rates, with a complete resection rate of 100% in the T group. In the C group, one case of incomplete partial resection led to recurrence during follow-up. Compared with the C group, the T group demonstrated statistically significant advantages in all perioperative indicators: shorter surgery time (79.10 ± 22.49 min vs. 119.75 ± 17.81 min, P < 0.001), reduced intraoperative blood loss (35.43 ± 18.16 mL vs. 92.50 ± 20.93 mL, P < 0.001), lower postoperative VAS scores (2.76 ± 0.70 vs. 6.40 ± 1.10, P < 0.001), shorter time to oral intake (2.19 ± 0.40 days vs. 3.85 ± 1.42 days, P < 0.001), and shorter hospital stay (3.86 ± 1.39 days vs. 7.40 ± 1.10 days, P < 0.001). The T group recorded only one transient Clavien-Dindo Grade II complication. In contrast, the C group experienced eight complications, including four severe events: one Grade IIId (permanent nerve damage), one Grade IIIb (vascular injury requiring reoperation), and two Grade IIIa events (abscess requiring drainage).

In this study, although both surgical strategies effectively resected tumors, TOES + ENS was associated with significantly superior safety profiles, characterized by the absence of severe complications and markedly improved postoperative recovery outcomes. Despite the limitations inherent to the retrospective design and small sample size, these findings support TOES + ENS as a valuable and potentially superior surgical option compared to traditional methods for appropriately selected patients with tumors in the parapharyngeal space.

Overall survival is used to assess clinical effectiveness in cancer clinical trials. In practice, it may be influenced by intercurrent events post-randomisation. The decisions made on how to address intercurrent events, change the interpretation of the results. An example is when participants stop their trial intervention and start subsequent anti-cancer interventions (treatment lines) during trial follow-up. At present, there is no evidence on the views of all stakeholders about this intercurrent event or consensus on how it should be addressed. The aim of this work was to understand the perspectives of all stakeholders and to obtain consensus through a qualitative study to guide future methodological work.

A modified Rand/UCLA appropriateness method was implemented. Stakeholder views were collected using an online questionnaire and discussed at a focus group. The questionnaire included items on, the different methods for addressing an intercurrent event, data collection following an intercurrent event, statistical assumptions, and data presentation. Analysis was descriptive incorporating a conventional content approach. Consensus was defined a priori.

One hundred three stakeholders (30 statisticians or other data analysts, 6 payers or industry partners, 22 healthcare professionals and 45 patient, carer or members of the public) completed the questionnaire between 3/8/2022 and 30/9/2022. Seventy-nine percent of respondents thought it important to consider the potential effect of subsequent treatment lines. Consensus was reached on most questionnaire items. Stakeholders agreed that statistical assumptions were applicable only in "Some Scenarios" and that results should be presented using both a visual and summary measure. The focus group discussed different methods for addressing an intercurrent event and items around data collection where consensus was unclear. Seven participants attended (two patients/carers, one healthcare professional, three statisticians and one payer) with K-LR and PW. Attendees agreed that the treatment policy approach should be considered in future work as it was the most realistic, and that data collection was acceptable with informed consent.

This work demonstrates that all stakeholder groups are interested in how subsequent treatment lines may impact overall survival and provides evidence on what future methodological work in the area should consider. The next step of this work will investigate whether it is possible to estimate the overall survival treatment effect in a hypothetical scenario where participants who received second-line therapy all received the same second-line therapy. This will aim to complement the existing treatment policy approach and quantify the impact of subsequent treatments.

Microwave ablation is a well-established therapeutic option for percutaneous treatment of lung tumors, however transbronchial microwave ablation remains under investigation. Our study aims to evaluate the safety and feasibility of transbronchial microwave ablation for lung cancer using state of the art bronchoscopy and imaging platforms and a microwave ablation system featuring tumor permittivity feedback control.

This study is an investigator initiated multicenter prospective diagnose-stage-treat, then resect, trial designed to evaluate the safety and feasibility of bronchoscopic microwave ablation. Patients with surgically resectable, treatment-naïve primary lung cancer tumors ≤ 3.0 cm will undergo shape sensing robotic assisted bronchoscopy (ssRAB) with cone-beam CT imaging for diagnostic sampling. Following intraoperative pathologic verification of malignancy, transbronchial microwave ablation will be performed. Cone-beam CT imaging will be used for verification of microwave probe position and for evaluation of ablation zone. Dedicated CT chest will be performed two weeks post-ablation. Two to four weeks following ablation patients will undergo standard of care surgical resection. Post-resection histopathologic analysis will evaluate treatment effect. Enrollment began March 2024 as a single-center study. The study will transition to multi-center to increase recruitment and improve generalizability.

This study will be a first of its kind using shape sensing robotic assisted bronchoscopy and cone-beam CT for transbronchial microwave ablation. Our treat and resect design will provide short-term clinical safety data and vital treatment effect data.

This trial is registered at ClinicalTrials.gov (Identifier: NCT05281237 ). This study was prospectively registered on March 15, 2022.

Surgical management of low rectal cancer can be challenging, particularly when postoperative complications such as anastomotic leakage and ischemia arise. This case report highlights the use of an ileal J-pouch interposition as an innovative solution in a patient with compromised colonic length and perfusion.

We present the case of a 50-year-old female patient with diabetes who underwent an intersphincteric resection, coloanal anastomosis, and appendicostomy, followed by an Antegrade Colonic Enema (ACE) for T2N0 rectal adenocarcinoma in November 2020. Postoperatively, she developed anastomotic leakage and a rectovaginal fistula due to ischemia, requiring a second surgery. Intraoperatively, the left and transverse colon were ischemic, leaving only the right colon viable, perfused by the ileocolic artery. Due to insufficient length for coloanal anastomosis, an ileal J-pouch was created and anastomosed to the anal canal, with the right colon connected to the pouch. The patient has achieved favorable long-term oncologic and functional outcomes, maintaining good bowel control with loperamide and ACE.

This case underscores the complexities of surgical management in low rectal cancer and the potential use of ileal J-pouch interposition as an effective solution for complications arising from primary surgical efforts. Further long-term studies are warranted to evaluate the sustainability of this approach in similar patient cohorts.

Pseudomyxoma peritonei (PMP) is a rare neoplastic disease that can occasionally present with pulmonary metastases as an even rarer manifestation. Although cytoreductive surgery represents the primary treatment option for PMP, surgical management of pulmonary metastases presents unique challenges owing to their mucinous nature. The aim of this case series was to present key considerations for the surgical management of PMP lung metastases, particularly regarding solid-appearing nodules that are impalpable during surgical resection, requiring more extensive resection owing to the risk of recurrence.

Between November 2013 and May 2023, we performed a total of 13 surgical procedures for pulmonary metastases in seven patients with PMP at our institution. During these procedures, 18 pulmonary lesions were resected. Some patients underwent multiple surgeries; multiple lesions were resected in a single procedure in certain cases. Notable characteristics of PMP pulmonary metastases, attributed to their mucinous dissemination pattern, included cases wherein subpleural solid nodules that would typically be palpable in patients with conventional solid tumour metastases were non-palpable and cases requiring right upper lobectomy following repeated surgical margin recurrence. Median follow-up results showed a progression-free survival of 20.0 months and overall survival of 40.3 months. Three of the seven patients experienced postoperative recurrence, with two patients having intrapulmonary metastatic recurrence involving low-grade tumours.

Surgical resection can be an effective treatment option for PMP pulmonary metastases; however, careful patient selection and appropriate surgical planning are essential. The unique characteristics of PMP metastases necessitate specific surgical strategies. Since computed tomography-apparent solid nodules may be non-palpable intraoperatively and surgical margin recurrence should be avoided, selecting surgical approaches that minimise unnecessary lung palpation, such as preoperative marking or anatomical lung resection, is crucial. The mechanisms of PMP pulmonary metastasis development and progression remain unclear, warranting further research into blood-borne dissemination patterns and optimal surgical techniques for non-palpable lesions.

Camrelizumab (an anti-programmed cell death protein-1 antibody) combined with apatinib (an antiangiogenic agent) has conferred benefits for advanced NSCLC. This study aimed to assess the efficacy and safety of camrelizumab and apatinib alongside chemotherapy in patients with resectable stage IIIA (N2) NSCLC as neoadjuvant therapy.

Patients with stage IIIA (N2) NSCLC were treated with a combination of chemotherapy, camrelizumab (200 mg, once every 3 weeks [q3w]), and apatinib (250 mg, once daily). Surgery was planned after 2-4 cycles of therapy. The primary endpoint was major pathological response (MPR) rate, with secondary endpoints including pathological complete response (pCR) rate, R0 resection rate, objective response rate (ORR), and safety. The trial was registered at ChiCTR.org.cn (ChiCTR2200059608).

Thirty-one patients were enrolled from August 4, 2021, to October 8, 2023. The disease control rate (DCR) was 93.5%, while the ORR was 87.1% and a clinical down-staging rate of 19.4%. Among them, 20 patients underwent complete resection, the MPR rate was 65.0%, and the pCR rate was 40%. Any grade neoadjuvant adverse events (AEs) were reported in 31 (100%) of the patients, and grade 3/4 AEs in 19 (61.3%). The most common AEs of any grade were fatigue (61.3%), nausea (54.8%), and decreased white blood cell count (51.6%). These conditions typically return to normal within a short period following observation or pharmacological treatment. No treatment-related deaths occurred.

The synergistic application of chemotherapy with camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a promising therapeutic alternative for individuals with resectable stage IIIA (N2) NSCLC.