PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.

While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

Primary extraperitoneal hydatid cyst, a rare differential diagnosis of subdiaphragmatic mass: A case report.

Key Clinical Message: Hydatid cyst is a sly disease that can manifest with a spectrum of symptoms in almost every part of the human body, so it is crucial to be familiar with different scenarios that a patient may present. Abstract: The echinococcus granulosus parasite causes hydatid disease and is common in areas with animal husbandry and agriculture. Here, we report a middle age woman who presented with abdominal pain that further investigation revealed a cyst in subdiaphragmatic area.

Effectiveness of autologous fibrin glue in preventing post-thoracotomy air leaks: a randomized controlled trial.

Introduction: Post-thoracotomy air leaks remain a significant challenge in thoracic surgery. Aim: This randomized controlled trial assessed the efficacy of autologous fibrin glue in reducing air leaks following thoracotomy procedures. Material and methods: Conducted as a single-center, single-blind, randomized clinical trial, the study enrolled adult patients undergoing lung resection or decortication at a thoracic surgery clinic. Participants were randomly assigned to either the intervention group, receiving autologous fibrin glue application during surgery, or the control group, undergoing standard surgical procedures without glue application. Key inclusion criteria were adult patients undergoing elective thoracotomy for lung resection or decortication, while exclusion criteria included patients with severe comorbidities or contraindications to fibrin glue. Results: A total of 40 patients were enrolled and randomized equally to the two groups. The group treated with autologous fibrin glue demonstrated a significant reduction in the duration of air leakage and chest tube drainage, along with a shorter hospital stay, compared to the control group. There were no statistically significant differences in postoperative complications between the groups. Conclusions: The application of autologous fibrin glue during thoracotomy procedures significantly reduces postoperative air leaks and hospitalization duration without increasing complication rates. This finding suggests a beneficial role of fibrin glue in thoracic procedures requiring lung resection or decortication.

Radiographic Investigation of Lumbar Vertebrae in Patients with Flexion and Extension Movement Disorder Syndrome.

Objectives: The kinesiopathology model is a new rehabilitation model classifying, evaluating, and treating patients with non-specific back pain. Sahrmann proposed this model based on movement disorder syndromes. The present cross-sectional study aimed to evaluate the radiograph of the linear and angular displacement of the lumbar spine in patients with lumbar flexion impairment syndrome (LFIS) and lumbar extension impairment syndrome (LEIS). Methods: In this study, 50 adults aged 18-46 years were enrolled, including 25 patients with LFIS and 25 with LEIS. The eligible participants were referred to the radiology department for radiography in the common position of neutral, full extension, and full flexion position while standing. The White and Panjabi's method was used to measure the linear and angular displacements. Moreover, pain intensity was assessed using the visual analogue scale, and functional disability was investigated using a modified Oswestry Disability Questionnaire. Results: The parameter of the linear displacement at the L3-L4 level was significantly different between the two groups (P=0.02). The mean duration of low back pain was longer in the LEIS, compared to the LFIS group (P=0.01). Conclusion: In patients with LEIS, compensatory responses occur that cause less linear displacement at the L3-L4 level, compared to the patients with LFIS. Therefore, it is important to design appropriate exercises to better control the linear displacement at the L3-L4 level during the full range of motion in patients with LFIS.

Optimal delivery of RNA interference by viral vectors for cancer therapy.

In recent years, there has been a surge in the innovative modification and application of the viral vector-based gene therapy field. Significant and consistent improvements in the engineering, delivery, and safety of viral vectors have set the stage for their application as RNA interference (RNAi) delivery tools. Viral vector-based delivery of RNAi has made remarkable breakthroughs in the treatment of several debilitating diseases and disorders (e.g., neurological diseases); however, their novelty has yet to be fully applied and utilized for the treatment of cancer. This review highlights the most promising and emerging viral vector delivery tools for RNAi therapeutics while discussing the variables limiting their success and suitability for cancer therapy. Specifically, we outline different integrating and non-integrating viral platforms used for gene delivery, currently employed RNAi targets for anti-cancer effect, and various strategies used to optimize the safety and efficacy of these RNAi therapeutics. Most importantly, we provide great insight into what challenges exist in their application as cancer therapeutics and how these challenges can be effectively navigated to advance the field.

Tension pneumothorax caused by the ruptured hydatid cyst of the lung.

Hydatid cyst disease puts a significant burden on the health of humans every year. The lung is the second most common organ of implantation of Echinococcus larvae. Due to the importance of early diagnosis of tension pneumothorax, this paper provides four cases of hydatid disease that presented with tension pneumothorax.

Tracheal hemangioma: a case report and literature review.

Hemangiomas are the most common vascular tumors in children. Although hemangiomas are common, they are rarely seen in areas like the trachea and larynx.The most common clinical manifestations in tracheal hemangiomas are stridor and respiratory distress. The main diagnostic method is bronchoscopy. Other imaging techniques like computed tomography scans and MRIs are also helpful. Various treatment options are now used for treating the disease, including beta blockers like propranolol, local and systemic steroids, and surgical resection. Case presentation: An 8-year-old boy with the chief complaint of severe progressive dyspnea and a history of neonatal postbreastfeeding cyanosis was admitted. On physical examination, he had tachypnea, and stridor was heard upon auscultation. There was no history of fever, chest pain, or coughing. He underwent a rigid bronchoscopy followed by a neck computed tomography scan. The results indicated a soft tissue mass with a vascular nature. An MRI of the neck confirmed the diagnosis of tracheal hemangioma. The mass was not resectable during surgery; hence, angioembolization was carried out. Treatment was successful and there was no recurrence on the follow-up. Clinical discussion: Based on the findings in this literature review tracheal hemangiomas present with stridor, progressive respiratory distress, dyspnea, hemoptysis, and chronic coughs. Advanced tracheal hemangiomas commonly do not reduce in size by themselves and need treatment. A close follow-up ranging from 3 months to 1 year is recommended. Conclusion: Although tracheal hemangiomas are rare they should be considered in the differential diagnosis of severe dyspnea and stridor.

Synthetic virology approaches to improve the safety and efficacy of oncolytic virus therapies.

The large coding potential of vaccinia virus (VV) vectors is a defining feature. However, limited regulatory switches are available to control viral replication as well as timing and dosing of transgene expression in order to facilitate safe and efficacious payload delivery. Herein, we adapt drug-controlled gene switches to enable control of virally encoded transgene expression, including systems controlled by the FDA-approved rapamycin and doxycycline. Using ribosome profiling to characterize viral promoter strength, we rationally design fusions of the operator element of different drug-inducible systems with VV promoters to produce synthetic promoters yielding robust inducible expression with undetectable baseline levels. We also generate chimeric synthetic promoters facilitating additional regulatory layers for VV-encoded synthetic transgene networks. The switches are applied to enable inducible expression of fusogenic proteins, dose-controlled delivery of toxic cytokines, and chemical regulation of VV replication. This toolbox enables the precise modulation of transgene circuitry in VV-vectored oncolytic virus design.

Hydatid cyst of the middle mediastinum complicated by fistulated ascending aorta: A case report and review of the literature.

Clinicians must pay attention to the clinical presentation and consequences of hydatid cysts in rare sites. Cysts close to the aorta require planning and assistance of a cardiac or vascular surgeon before surgical intervention can be considered.

Fatty acid transport protein inhibition sensitizes breast and ovarian cancers to oncolytic virus therapy via lipid modulation of the tumor microenvironment.

Introduction: Adipocytes in the tumour microenvironment are highly dynamic cells that have an established role in tumour progression, but their impact on anti-cancer therapy resistance is becoming increasingly difficult to overlook. Methods: We investigated the role of adipose tissue and adipocytes in response to oncolytic virus (OV) therapy in adipose-rich tumours such as breast and ovarian neoplasms. Results: We show that secreted products in adipocyte-conditioned medium significantly impairs productive virus infection and OV-driven cell death. This effect was not due to the direct neutralization of virions or inhibition of OV entry into host cells. Instead, further investigation of adipocyte secreted factors demonstrated that adipocyte-mediated OV resistance is primarily a lipid-driven phenomenon. When lipid moieties are depleted from the adipocyte-conditioned medium, cancer cells are re-sensitized to OV-mediated destruction. We further demonstrated that blocking fatty acid uptake by cancer cells, in a combinatorial strategy with virotherapy, has clinical translational potential to overcome adipocyte-mediated OV resistance. Discussion: Our findings indicate that while adipocyte secreted factors can impede OV infection, the impairment of OV treatment efficacy can be overcome by modulating lipid flux in the tumour milieu.

Primary retroperitoneal hydatid cyst, a rare novel differential diagnosis of retroperitoneal masses: A case report.

The presence of primary retroperitoneal hydatid cysts is rare, even in endemic areas. The authors report a young man with a retroperitoneal hydatid cyst who underwent total cystectomy. The surgeons should suspect hydatid cysts in case of any abdominal cysts, especially in endemic areas, and avoid any spillage and puncture.

Branched-chain amino acids regulate intracellular protein turnover in porcine mammary epithelial cells.

Dietary supplementation with branched-chain amino acids (BCAAs) to lactating sows has been reported to enhance their milk production, but the underlying mechanisms remain largely unknown. This study was conducted with porcine mammary epithelial cells (PMECs) to test the hypothesis that individual BCAAs or their mixture stimulates protein synthesis and inhibit proteolysis in PMECs. Cells were cultured at 37 °C in customized Dulbecco's modified Eagle medium containing 5 mmol/L D-glucose, 1 mmol/L L-phenylalanine, L-[ring-2,4-3H]phenylalanine, 0.1 (control), 0.25, 0.5, 1, or 2 mmol/L L-leucine, L-isoleucine or L-valine or an equimolar mixture of the three BCAAs. The culture medium also contained physiological concentrations of other amino acids found in the plasma of lactating sows. Proliferation, protein synthesis, proteolysis, ß-casein production, the mechanistic target of rapamycin (mTOR) signaling, and the ubiquitin-proteasome pathway were determined for PMECs. Cell proliferation and abundances of phosphorylated mTOR, eukaryotic translation initiation factor 4E-binding protein 1, and ribosomal protein S6 kinase ß-1 proteins increased (P < 0.05), but abundances of ubiquitinated protein and 20S proteasome decreased (P < 0.05) when extracellular concentrations of L-leucine, L-isoleucine, L-valine, or an equimolar mixture of BCAAs were increased from 0.1 to 2 mmol/L. Compared with the control, 0.25, 0.5, 1 or 2 mmol/L BCAAs enhanced (P < 0.01) protein (including ß-casein) synthesis, while decreasing (P < 0.05) proteolysis in PMECs in a dose-dependent manner. Collectively, our results indicate that physiological concentrations of BCAAs regulate protein turnover in mammary epithelial cells to favor net protein synthesis through stimulating the mTOR signaling pathway and inhibiting the ubiquitin-proteasome pathway.

Exposure keratopathy and its associated risk factors in patients undergoing general anesthesia in nonocular surgeries.

INTRODUCTION: The most common eye injury during and after general anesthesia is corneal abrasion which can occur at any time after anesthesia and even up to 24 h after it. The aim of this study was to investigate the incidence and factors associated with corneal injury in patients undergoing nonocular surgery. METHODS: This was a descriptive cross-sectional study. A total of 170 patients, who were admitted to the operating room and met the inclusion criteria, were selected through simple nonprobability sampling. Data collection forms were used in order to assess the incidence of corneal injury and its related risk factors. The National Eye Institute scale with fluorescein paper and cobalt blue light by slit lamp were utilized to examine exposure keratopathy. RESULTS: Overall, the results showed that the incidence of keratopathy immediately after eye care removal was found to be 64.7% in the operating room, 65.9% in the recovery room, and 41.2% in 24 h after the surgery. Smokers' patients and drug abusers under general anesthesia underwent endotracheal intubation, received more opioids preoperatively, and had more perioperative bleeding and fluid intake. Moreover, in patients who had received more oxygen flow in the recovery room; the rate of keratopathy was higher. CONCLUSION: Smoking, drug usage, and receiving endotracheal intubation are the risk factors of keratopathy. Therefore, for high-risk patients and procedures, it is indispensable to both obtain preoperative information and take intraoperative precautions in order to prevent eye injuries. Future studies are needed to demonstrate these finding.

Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy.

Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or "cancer-killing" viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.

Surgical Repair of Atrial-Esophageal Fistula Following Catheter Ablation.

Left atrial-esophageal fistula after radiofrequency ablation for atrial fibrillation is a rare and potentially lethal complication. Although surgical management is associated with improved outcomes, the optimal approach remains to be elucidated. We describe a case of atrial-esophageal fistula treated with a simultaneous repair of the atrium and esophagus via a right thoracotomy with an extrapericardial off-pump approach.

Comparison of transhiatal esophagectomy using a mediastinoscope with transhiatal esophagectomy by the classic method.

BACKGROUND: This study aimed to evaluate the results of transhiatal esophagectomy using a mediastinoscope in comparison with conventional transhiatal esophagectomy. METHODS: Sixty-two esophageal cancer patients who were referred to our thoracic surgery clinic between April 2015 and March 2017, and met the inclusion criteria, were randomly divided into two groups of 31 each. In the first group, patients were operated on by conventional transhiatal esophagectomy. In the second group, only release of the thoracic esophagus through a neck incision (mediastinal esophagolysis) was performed using a mediastinoscope. The other surgical procedures were similar to those in the first group. RESULTS: The mean age of the patients was almost the same in both groups (57.7 years in the first group versus 56.7 years in the second group). There was no significant difference in sex ratio. The mean volume of blood loss during the operation, mean operative time, and intensive care unit stay as well as cardiopulmonary complications and early postoperative complications were lower in the group that had esophagectomy using a mediastinoscope, and the number of resected mediastinal lymph nodes was greater. CONCLUSION: Based on the results of this study, it can be expected that use of a video mediastinoscope for esophagolysis of the thoracic esophagus in a transhiatal esophagectomy procedure is safe and it will reduce the morbidity and mortality in these patients.