bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precise activation of antiviral memory T cells in solid tumors triggers a multi-cytokine response that ultimately drives tumor clearance
Authors: Gavil Noah Veis , Smith Olivia , Weyu Eyob , Joag Vineet , Vezys Vaiva , Masopust David 
Published: August 2023

Abstract
The reactivation of CD8+ tissue-resident memory T cells (TRM) triggers a broad, yet local response that mobilizes adaptive and innate immune cells. This immunostimulatory process can be initiated in solid tumors when infiltrating antiviral memory T cells are reactivated. The intratumoral delivery of viral peptides is sufficient to clear poorly immunogenic tumors in mice and synergizes with immune checkpoint therapy. This study investigated the mechanisms required for this anti-tumor response and novel “Peptide Alarm Therapy” that is currently being tested in a Phase I clinical trial. In contrast to expectations, viral peptide presentation by cancer cells was not required for treatment efficacy, and while NK and CD4 T cells are activated and/or recruited to the tumor microenvironment (TME) following antiviral memory T cell activation, depletion of either population did not limit tumor clearance. Interestingly, inflammatory monocytes were greatly increased in both the TME and tumor-draining lymph node (tdLN) following therapy. Moreover, antigen presenting cells (APCs) containing tumor-derived antigen accumulated within the tdLN. TNFα, IFNγ, and IL-2 are cytokines that can signal to APC populations and are produced by activated TRM. When these cytokines were blocked collectively, but not independently, the treatment efficacy of Peptide Alarm Therapy was greatly reduced. Further, when these cytokines were intratumorally injected, they recapitulated some phenomena achieved by antiviral T cell activation. Thus, local reactivation of antiviral memory T cells, which infiltrate tumors and possess known specificities, drives a multi-cytokine response that promotes the immune-stimulation that effectuates tumor clearance.
1R01CA238439-01A1, 1F30CA253992-01
Tumor cell secretome induces the expression of the immune checkpoint NKG2A on CD8+ T cells
Authors: Rodriguez-Garcia Gabriel J , Schares Henry A , Bachmann Brian O , Kim Young J , Korrer Michael J , Rathmell Jeffrey C 
Published: August 2023

Abstract
PD-1 blockade has been approved for head and neck squamous cell carcinoma (HNSCC) patients. However, only about 20% of HNSCC patients respond to PD-1 blockade. We hypothesize that other inhibitory receptors play a role as a resistance mechanism to PD-1 blockade. Our laboratory and others found that the NKG2A/HLA-E pathway is overexpressed in HNSCC patients. NKG2A is an inhibitory receptor expressed by NK cells and CD8+ T cells. How NKG2A expression is regulated on human T cells is not clear. Additionally, we previously identified a significant increase in NKG2A+ T cells in the tumors when compared to T cells in matching PBMC samples. Therefore, we hypothesize that the tumor microenvironment is inducing NKG2A’s expression. We have identified that tumor conditioned media (TCM) of HNSCC cell lines induce the expression of NKG2A on activated CD8+ T cells isolated from PBMCs of healthy donors. In our efforts to identify what factor(s) in the TCM are inducing NKG2A, we boiled the TCM to denature proteins or used filters to exclude molecules larger than 3kDa. However, both boiled and filtered TCM show similar induction of NKG2A. In addition, we further divided the media through hydrophobic fractionation of the filtered TCM and showed NKG2A is induced by the most hydrophobic fraction. Altogether, these findings suggests that NKG2A is being induced by a heat stable small hydrophobic molecule. This is a novel mechanism for tumor immune evasion, in which tumor cells induce NKG2A expression through secretion of small molecules. Our findings can lead to targets for novel cancer therapies or biomarkers for NKG2A blockade response.
Supported by grant from NIH/NCI (R01 CA217987) and the T32 AI138932 “Immunological Mechanisms of Disease Training Program”.
Discovery of Human Papilloma Virus and patient-specific neoantigens targeted by CD8+ T cells in HNSCC
Authors: Makani Venkata Krishna Kanth , Li Housaiyin , Kulkarni Aditi , Arshad Sanya , Vujanovic Lazar , Ferris Robert L , Joglekar Alok V 
Published: August 2023

Abstract
Head and neck squamous cell carcinoma (HNSCC) is amongst the rapidly growing form of cancer associated with high mutation burden and Human Papilloma virus (HPV) infection presenting approximately 800,000 new cases and 400,000 deaths annually. HPV-positive (HPV) HNSCC has been strongly associated with better prognosis than HPV-negative HNSCC due to the immune activation in the tumor microenvironment including cytotoxic CD8+ T cells. One of the key missing links is the relative contribution of HPV-reactive and neoantigen-reactive CD8+ T cells in anti-tumor response. To address this, we utilized epitope libraries presented in Signaling and Antigen-presenting Bifunctional Receptors (SABRs), which were previously described by our lab. As a proof-of-concept, we generated SABR libraries presenting 8392 epitopes derived from HPV or from personalized neoantigens from five HNSCC patients. In parallel, we used single cell RNA sequencing to identify 25 clonally expanded TCRs from tumor-infiltrating lymphocytes of the patients. Using SABR screens, we have identified several putative HPV-derived and neoantigen-derived epitopes targeted by CD8+ T cells in HNSCC patients. We have established a robust pipeline for identification of patient-specific epitope specificities from tumor-infiltrating CD8+ T cells. The goal is to determine whether and how effective anti-HPV or anti-neoantigen T cell responses may contribute to therapeutic efficacy using human samples from clinical trials and murine HNSCC models. Our study will aid in the discovery of novel tumor-associated antigens in HPV+ HNSCC patients, which can be successfully employed for precise adoptive T cell transfer therapies.
Generation of repetitive element-specific T cells to target ovarian cancer
Authors: Grundy Erin E , Cox Olivia , Lee Abigail , Omar Khadra , Chiappinelli Katherine Bakshian 
Published: August 2023

Abstract
The immunosuppressive tumor microenvironment in ovarian cancer (OC) enables these tumors to evade the immune system, resulting in late diagnosis and poor therapeutic outcomes for patients. This immunosuppression can be partially reversed with epigenetic inhibitors, which stimulate an immunogenic interferon response in OC cells by inducing the transcription of repetitive elements (REs). However, epigenetic therapy alone is not curative in clinical trials and new treatments that further augment the immune response to OC are needed. While REs are epigenetically silent in terminally differentiated cells, their increased expression in OC cells implicate these genomic elements as an unexplored pool of tumor antigens. As epigenetic therapy also upregulates antigen processing and presentation in OC cells, the generation of T cells specific for over-expressed RE-derived antigens may boost the immune recognition of OC cells.
Transducing healthy donor T cells with a T cell receptor construct that recognizes the RE ERV-K-Env resulted in antigen specificity only when co-cultured with B lymphoblastoid cells derived from the same donor that the T cell receptor was isolated from. Transduced T cells were not specific for ERV-K-Env in autologous systems. As previous reports have shown that ERV-K-Env-specific T cells can only be expanded from patients with OC, current studies are underway to expand T cells from OC patients. Upon successful expansion of ERV-K-Env-specific T cells from multiple OC patients, we will assess if specific recognition is enhanced by treating autologous tumor cells with epigenetic therapy. These efforts serve as a novel approach to enhance the immune response to OC and improve the overall OC patient survival rate.
NIH F31 CA271788-01 DOD W81XWH2010273
NCG-MHC-dKO mice - an excellent model for PBMC reconstitution and pharmacodynamic evaluation in the absence of GvHD
Authors: Chen Santi Suryani , Wang Huiyi , Xing Jun , Fan Jialu , Hou Huanhuan , Li Zhiying , Moore Mark , Zhao Jing , Xiang Gao , Ju Cunxiang 
Published: August 2023

Abstract
Human immune cell reconstitution (Peripheral Blood Mononuclear Cells; PBMC or CD34+ hematopoietic stem cell; HSC) is commonly performed in immunodeficient mouse strains, such as NCG, NSG, or NOG. Human immune reconstitution utilizing PBMCs is a much more rapid model, allowing for T-cell reconstitution within 2 weeks. Due to the occurrence of xenogeneic graft-versus-host disease (xGvHD) around 4 weeks post-engrafment, the application of PBMC-reconstituted NCG mice is relatively limited.
xGvHD is mainly induced by T cells derived from donor PBMC engraftment recognizing the murine host MHC class I and class II as foreign and attacking the host cells and organs. Deleting the β2m (NCG-β2m-KO) could reduce the occurrence of xGvHD; however, β2m is not only in the MHC class I subunit but also in the FcRn subunit, of which deletion shortens the half-life of IgG, making it unsuitable for IgG antibody agent evaluation. In addition, the deletion of MHC class I or class II alone results in an imbalanced CD4/CD8 ratio. To solve these problems, we developed the NCG-MHC-dKO mouse model by knocking out the H2K1, H2D1, and H2Ab1 genes. Compared with the existing NCG-B2m-KO mouse model, the NCG-MHC-dKO significantly prolonged survival, reduced xGvHD occurrence, and did not affect the CD4/CD8 ratio when reconstituted with PBMC. Furthermore, treatment with anti-PD-L1 antibodies significantly inhibited MDA-MB-231 tumor cell growth in PBMC-reconstituted NCG-MHC-dKO mice, similar to NCG mice. Based on our preliminary data, the NCG-MHC-dKO mouse is a promising model for evaluating antibody and cell therapy agents, assessing treatment-related cytokine release syndrome, and evaluating long-term toxicities of cell therapies.
The Effectiveness of Combined Local and Systemic Methotrexate Treatment in Cesarean Scar Pregnancy Weeks 8 to 14
Authors: Van Xuyen , Bui Thuong , Dinh Hoang The , Van Thong , Tran Anh 
Published: August 2023

Objectives:
This study aims to identify the success rate and correlated factors of combined local and systemic methotrexate (MTX) injection treatment in cesarean scar pregnancy (CSP).

Materials and Methods:
The combined local and systemic MTX administration has been used for CSP weeks 8–14 at Tu Du Maternal Hospital; however, its effectiveness and correlated factors have not been closely investigated. This is a retrospective case series of 123 CSP patients between 8 and 14 weeks of gestation who were treated at Tu Du Hospital from the year 2016 to 2020.

Results:
The success rate, uterine-sparing rate, and side effects of MTX treatment are 50.4%, 95%, and 17.2%, respectively. The factors related to treatment failure with statistical significance included gestational age (odds ratio [OR] = 3.99), residual myometrial thickness >3 mm (OR = 0.37), and postprocedure gestational sac diameter (OR = 1.09).

Conclusion:
Combined local and systemic MTX injection is minimally invasive and effective in CSP weeks 8–14. Therefore, it should be utilized routinely.
Association of heavy metals and trace elements in carcinoma urinary bladder: A case-controlled study
Authors: Panaiyadiyan Sridhar , Quadri Javed Ahsan , Nayak Brusabhanu , Pandit Surabhi , Singh Prabhjot , Sachan Ankit , Kaushal Seema , Sarwar Saba , Seth Amlesh , Shariff Ahmadullah 
Published: August 2023

Introduction:
Abnormal levels of heavy metals (HM) and trace elements (TE) affect body metabolism and can induce carcinogenesis. This study aims to evaluate the role of HM and TE in carcinoma urinary bladder (CAUB).

Methods:
Patients with biopsy-proven CAUB (n = 100) were taken as the study group, while age-and sex-matched healthy volunteers were taken as control (n = 100). Blood and urine samples were compared for Arsenic (As), Copper (Cu), Manganese (Mn), Selenium (Se), Cadmium (Cd), Lead (Pb), and Mercury (Hg) levels. Serum glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and lipid peroxidation (LPO) levels were assessed to know the redox status between the two groups.

Results:
A significantly higher blood level of As, Mn, and Pb was observed in CAUB cases as compared to controls. Blood Se level was significantly lower in CAUB patients. On comparing urinary levels, CAUB patients had a higher As, Mn, and Pb levels compared to controls. Further, 68% and 59% of patients had their blood and urinary HM and TE levels above the permitted level, respectively. CAUB cases also had a lower GSH-Px (113.5 ± 44.7 vs. 163.9 ± 120.5, P = 0.0002), lower SOD levels (11.35 ± 5.6 vs. 13.75 ± 3.9, P = 0.008), and a higher LPO levels (15.5 ± 14.7 vs. 11.18 ± 11.2, P = 0.02) in the serum.

Conclusions:
A significantly higher concentration of As, Mn, and Pb was noted in the blood and urine of CAUB patients compared to controls. CAUB cases also had lower serum GSH-Px and SOD levels with a concomitant increased serum LPO assay suggesting underlying oxidative stress.
Comparison of outcomes after open versus robotic kidney transplantation: A systematic review and meta-analysis
Authors: Madhavan Kumar , Jena Rahul , Bhargava Priyank , Pradhan Aditya , Bhandari Mahendra 
Published: August 2023

Introduction:
This meta-analysis compares the clinical outcomes of robot-assisted kidney transplant (RAKT) to open kidney transplant (OKT).

Methods:
A systematic search of Scopus and MEDLINE databases was carried out using a combination of keywords to identify studies comparing RAKT to OKT. Baseline characteristics and preoperative and postoperative data were collected along with data on the short- and long-term outcomes. The study was registered in PROSPERO and Assessing the Methodological Quality of Systematic Reviews and Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed.

Results:
A total of 16 studies were included with a total of 2555 patients, of which 677 underwent RAKT and 1878 underwent OKT. This meta-analysis shows a significant benefit of RAKT over OKT in terms of less intra-operative blood loss, smaller incision length, less postoperative pain scores at 24 and 48 hours, and a lower incidence of surgical site infections (SSIs), especially in obese patients. In addition, the incidence of postoperative lymphoceles was lower in the RAKT group compared to the OKT group, although not statistically significant. There was no difference between the two groups in terms of short-term graft functional outcomes and overall survival. The number of deceased donor recipients undergoing RAKT was very small. At the time of reporting this meta-analysis, no randomized controlled trials (RCTs) had been published.

Conclusion:
This meta-analysis showed that RAKT is a safe and feasible alternative to OKT, especially in obese individuals. Further trials are needed to confirm the safety, efficacy, and cost-effectiveness of RAKT.
Rare case of post-vertebroplasty fungal spondylodiscitis: Case report
Authors: K C Avinash , Mehta Satyen 
Published: August 2023

Abstract
Vertebroplasty is a commonly done procedure in osteoporotic compression fracture. Cement leakage is the most common complication associated with vertebroplasty. Infection following vertebroplasty is rare. Fungal spondylodiscitis following vertebroplasty has not been reported in the literature. The objective of this clinical case report was to highlight this rare fungal spondylodiscitis following vertebroplasty. A 67-year-old woman was diagnosed with osteoporotic compression fracture for which vertebroplasty was done. During the procedure, the primary surgeon noticed the cement leakage without any neurological complication. The patient was referred to us. The patient was diagnosed with spondylodiscitis with cement leakage. We performed an open biopsy with cement removal with posterior thoracic decompression and interbody fusion. On microbiological examination, Aspergillus fumigatus were isolated from multiple samples that were susceptible to voriconazole. On 1-month follow-up, patient’s pain significantly reduced with normalized inflammatory markers. Presence of immunocompromised status with diabetes mellitus and lack of quality operating theater with inadequate maintenance of sterility protocols during the procedure could be the reason for the infection.
Multiple sporadic spinal hemangioblastoma at the filum terminale and cervicodorsal junction: A case report and review of literature
Authors: Gurjar Hitesh , Gaonkar Vibha , Bansal Tungish , Borkar Sachin 
Published: August 2023

Abstract
Hemangioblastomas are low-grade tumors that frequently occur in the posterior fossa. Only 1%–5% of these tumors occur in the spinal cord and there are a handful of cases of filum terminale hemangioblastomas described in the literature. Here, we present a case with two spinal hemangioblastomas at filum terminale and cervicodorsal junction of sporadic origin. A 28-year-old woman presented with low back pain radiating to right lower limb with weakness of both lower limbs and urinary incontinence. The findings of the examination revealed asymmetric quadriparesis with more weakness on the left side of the body. Magnetic resonance imaging revealed a cervicodorsal and lumbar T2 hyperintense lesion with flow voids. Imaging findings were suggestive of hemangioblastoma. En bloc excision of both the tumors was performed and the diagnosis was confirmed on histopathology. She had an uneventful postoperative course and complete neurological recovery at the final follow-up. Multiple sporadic spinal hemangioblastomas involving the filum terminale are a very rare entity. Complete surgical excision provides good relief of symptoms.
A rare case of priapism secondary to intervertebral disc prolapse: Case report and literature review
Authors: Sheth Sharvin K , Jhala Amit C 
Published: August 2023

Abstract
Lumbar canal stenosis (LCS) is characterized by narrowing of the central spinal canal or lateral recesses and foramina, leading to compression of nerve tissues. It causes neurogenic claudication, which manifests as back pain and variety of lower limb symptoms such as pain, tingling/numbness, or paresthesia on ambulation. A rare symptom of LCS is priapism, which is thought to occur due to parasympathetic dysfunction. We describe a case of a 45-year-old man, who presented with neurogenic claudication and intermittent priapism due to lumbar intervertebral disc prolapse, which resolved completely after surgical decompression, and literature review for the same.
Idiopathic spinal cord herniation—An extremely rare cause of paraparesis: Case report
Authors: De Smet Bernardo , Pinheiro Teresa , Fonseca Lino 
Published: August 2023

Abstract
Idiopathic spinal cord herniation is a rare disorder, consisting of a ventral displacement of the spinal cord through a dural defect. The resulting adhesion and vascular compromise lead to neurological impairment. We report the case of a 54-year-old male, with a previous urological surgery resulting in chronic vesical catheterization, with a worsening paraparesis associated with anesthesia below T10. The magnetic resonance imaging showed a ventral displacement of the spinal cord at T7/T8 with an enlarged posterior subarachnoid space at that level. A four-level laminotomy was performed followed by spinal cord herniation reduction and closure of the anterior dural defect with a dural replacement. The patient had a partial recovery of his motor deficits regaining his ability to walk with the support of a single crutch. The purpose of this study was to highlight the existence of this extremely rare cause of paraparesis, which is often misdiagnosed.
Postoperative Outcomes Following Surgical Stabilization of Rib Fractures Stratified by 5-Factor Modified Frailty Index
Authors: Saraswat Nirvana , Werwie Nicole , Wu Jin , Hery Danielle , Saunders Emily , Bundy Hannah , Elliott John O. , Goslin Brent , DeVoe William 
Published: August 2023

Objectives:
Surgical stabilization of rib fractures (SSRF) improves outcomes in patients with flail chest and displaced fractures with impaired pulmonary function. Elderly and frail patients with such injuries are at risk for significant morbidity and may benefit from SSRF. The 5-factor modified frailty index (mFI-5) is a validated predictor of postoperative outcomes. The purpose of this study is to evaluate the relationship between frailty and outcomes following SSRF at a tertiary care trauma center.

Methods:
A retrospective review of patients undergoing SSRF from 2015 to 2019. Patients over 18 years old with two or more displaced fractures were included in the study. Exclusion criteria were isolated fracture, traumatic brain injury, and pulmonary contusion. Frail patients were defined by an mFI-5 score 2 or greater. Chi-square analysis, Fischer's exact test, and Student's t-test were used for comparative analysis as appropriate. P < 0.05 was considered statistically significant.

Results:
One hundred and fifty-four patients met inclusion criteria. Forty-eight patients were designated frail and 106 nonfrail. The mean number of fractures was similar between frail and nonfrail groups (7.0 vs. 7.3, P = 0.685). Injury Severity Score was lower in the frail group (14.5 vs. 17.8, P = 0.02). Inpatient mortality (P = 0.312), rates of pneumonia, end-organ dysfunction, and surgical site infections were similar (P > 0.05). Intensive care unit admission (47.9% vs. 29.2%, P = 0.025) and tracheostomy rates (P = 0.009) were increased in the frail group. Frailty also increased the risk of prolonged mechanical ventilation >48 h on multivariate analysis.

Conclusion:
Frail patients, stratified using mFI 5 score, experienced similar rates of multiple postoperative outcomes, including mortality, but had increased rates of prolonged ventilation and tracheostomy. Despite observed but expected increased morbidity in these patients, the similar complication and mortality rates suggest a role for surgical stabilization of severe rib fractures in frail patients.
Prevalence and Correlates of Peripheral Neuropathy amongst Type 2 Diabetes Mellitus Patients – A Community-Based Epidemiological Study in a Town of Eastern India
Authors: Chakraborty Sumanta , Majumder Anirban 
Published: August 2023

Background:
Diabetic peripheral neuropathy (DPN) is a microvascular complication of type 2 diabetes mellitus (T2DM) which may be attributed to chronic uncontrolled hyperglycaemia. DPN increases the risk of foot ulcers and non traumatic amputations, leading to disability, morbidity and poor quality of life for the diabetics.

Aims:
This study aims to find out the prevalence of peripheral neuropathy amongst T2DM patients and ascertain the correlates for the same. Settings and Design: A cross sectional study was conducted amongst 104 diabetic individuals of Bankura city of West Bengal using principles of simple random sampling technique.

Materials and Methods:
Data on peripheral neuropathy were collected using Michigan Neuropathy Screening Instrument and correlates were assessed by a pre designed pre tested schedule consisting of background and socio demographic characteristics along with medication adherence rating scale.

Statistical Analysis Used:
Data were entered into Excel (Microsoft Inc.) and all calculations were done using IBM Statistical Package for the Social Sciences (SPSS) (Version 20.0, IBM). Data were analysed and presented using principles of descriptive and analytical statistics.

Results:
The prevalence of DPN was 59.1%. The presence of co morbidities, poor socio economic status, polypharmacy, food insecurity, catastrophic health expenditure and lack of social insurance were found significantly associated with DPN.

Conclusions:
DPN prevalence was found to be considerably high. Multiple factors were found to culminate it, upon which socio economic and health care affordability issues were prominent. A multi disciplinary approach focusing on them using Patients oriented evidence that matters approach, diabetes education and periodic screening of the diabetic population may help in mitigating the morbidity risks.