Unravelling the role of Silibinin in targeting CD44+ cancer stem cells: Therapeutic implications, effective strategies and approaches.

CD44+ cancer stem cells (CSCs) are believed to account for drug resistance and tumour recurrence due to their potential to self-renew and differentiate into heterogeneous lineages. Therefore, efficient treatment strategies targeting and eliminating these CSCs are required. The flavonolignan, Silibinin, has gained immense attention in targeting CD44+ CSCs as it alters functional properties like cell cycle arrest, apoptosis, inhibition of invasion and metastasis and also inhibits a range of molecular pathways. However, its limited bioavailability is a major hurdle in asserting Silibinin as a translational therapeutic agent. Combinatorial therapy of Silibinin with conventional chemotherapeutic drugs is an alternative approach in targeting CD44+ CSCs as it increases the efficacy and reduces the cytotoxicity of chemotherapeutic drugs, thus preventing drug resistance. Certain Silibinin-conjugated nano-formulations have also been successfully developed, through which there is improved absorptivity/bioavailability of Silibinin and a decrease in the concentration of therapeutic drugs leading to reduced cytotoxicity. In this review, we summarise the effectiveness of the synergistic therapeutic approach for Silibinin in targeting the molecular mechanisms of CD44+ CSCs and emphasise the potential role of Silibinin as a novel therapeutic agent.

Grassroots Approach to Forming a Diversity, Equity, and Inclusion Committee in an Academic Radiology Department.

Radiology is among the medical specialties that have made the fewest gains in closing the gap in underrepresented minorities and women. Diversity, equity, and inclusion (DEI) initiatives are important for promoting healthy learning environments for trainees, health equity for patients, and equitable career development opportunities for employees, all of which contribute to innovation in today's competitive health care environment. DEI committees can self-organize or form from institutional directives. These committees can implement impactful projects in multiple domains in education, recruitment and retention, department culture, and health equity research. This article describes the formation of a grassroots DEI committee, key initiatives and strategies, and structures for accountability. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Salivary Exosomal miRNA-1307-5p Predicts Disease Aggressiveness and Poor Prognosis in Oral Squamous Cell Carcinoma Patients.

Background: Salivary exosomal miRNAs as biomarkers facilitate repeated sampling, real-time disease monitoring and assessment of therapeutic response. This study identifies a single salivary exosomal miRNA prognosticator that will aid in improved patient outcome using a liquid biopsy approach. Method: Small RNA and transcriptome sequencing profiles of tumour tissues (n = 12) and salivary exosomes (n = 8) from oral cancer patients were compared to their non-cancerous counterparts. We validated these results using The Cancer Genome Atlas database and performing Real-time PCR on a large patient cohort (n = 19 tissue samples; n = 12 salivary exosomes). Potential target genes and the miRNA-mRNA networks and enriched biological pathways regulated by this microRNA were identified using computational tools. Results: Salivary exosomes (size: 30-50 nm) demonstrated a strong expression of CD47 and detectable expression of tetraspanins CD63, CD81 and CD9 by flow cytometry. miR-1307-5p was exclusively overexpressed in tissues and salivary exosomes of oral cancer patients compared to their non-cancerous counterparts. Enhanced expression of miR-1307-5p clinically correlated with poor patient survival, disease progression, aggressiveness and chemo-resistance. Transcriptome analysis suggested that miRNA-1307-5p could promote oral cancer progression by suppressing THOP1, EHF, RNF4, GET4 and RNF114. Conclusions: Salivary exosomal miRNA-1307-5p is a potential prognosticator for predicting poor survival and poor patient outcome in oral cancers.

A Study of Haematological Profile in Newly Diagnosed Rheumatoid Arthritis and its Correlation with Disease Activity.

Rheumatoid Arthritis is a chronic inflammatory disease of unknown etiology characterised by presence of symmetric involvement of multiple joints, mainly small joints that rapidly progresses to multisystem inflammation. Common haematological abnormalities observed are anemia,leucocytosis, neutropenia, thrombocytosis, thrombocytopenia, eosinophilia and haematological malignancies. This study is aimed at the various haematological parameters observed in newly diagnosed patients of rheumatoid arthritis and correlating it with disease activity measured by indices like DAS 28 CRP and HAQDI. MATERIAL: Patients more than 16 years of age and newly diagnosed cases of rheumatoid arthritis according to the ACR EULAR 2010 criteria who presented in the rheumatology opd were included in the study. A total of 20 patients fulfilling the inclusion criteria were studied.Any patient with active blood loss from any site, infection,chronic liver or kidney disease, malignancies,hematological diseases,those already on disease modifying drugs,other autoimuune diseases were excluded from the study. OBSERVATION: Out of 20 patients of rheumatoid arthritis studied,55%(11) had anemia of chronic disease and 27.5%(5) had iron deficiency anemia,3%(1) had eosinophilia. The disease activity was measured using DAS 28 CRP and HAQ DI. A negative correlation was observed between Hb level and disease activity whereas a positive correlation was observed between platelet count and disease activity. CONCLUSION: In our study it was observed that Hb is significantly lower in patients with high disease activity whereas platelet count and MPV are significantly higher with high disease activity compared to patients with low to moderate disease activity.So, from Hb level, platelet count and MPV, we can predict disease activity in RA patients which can guide us for proper and aggressive management to prevent further disease progression.

Attitudes of High Versus Low Antibiotic Prescribers in the Management of Upper Respiratory Tract Infections: a Mixed Methods Study.

IMPORTANCE: Inappropriate antibiotic use for upper respiratory tract infections (URTIs) is an ongoing problem in primary care. There is extreme variation in the prescribing practices of individual physicians, which cannot be explained by clinical factors. OBJECTIVE: To identify factors associated with high and low prescriber status for management of URTIs in primary care practice. DESIGN AND PARTICIPANTS: Exploratory sequential mixed-methods design including interviews with primary care physicians in a large health system followed by a survey. Twenty-nine physicians participated in the qualitative interviews. Interviews were followed by a survey in which 109 physicians participated. MAIN MEASURES: Qualitative interviews were used to obtain perspectives of high and low prescribers on factors that influenced their decision making in the management of URTIs. A quantitative survey was created based on qualitative interviews and responses compared to actual prescribing rates. An assessment of self-prescribing pattern relative to their peers was also conducted. RESULTS: Qualitative interviews identified themes such as clinical factors (patient characteristics, symptom duration, and severity), nonclinical factors (physician-patient relationship, concern for patient satisfaction, preference and expectation, time pressure), desire to follow evidence-based medicine, and concern for adverse effects to influence prescribing. In the survey, reported concern regarding antibiotic side effects and the desire to practice evidence-based medicine were associated with lower prescribing rates whereas reported concern for patient satisfaction and patient demand were associated with high prescribing rates. High prescribers were generally unaware of their high prescribing status. CONCLUSIONS AND RELEVANCE: Physicians report that nonclinical factors frequently influence their decision to prescribe antibiotics for URTI. Physician concerns regarding antibiotic side effects and patient satisfaction are important factors in the decision-making process. Changes in the health system addressing both physicians and patients may be necessary to attain desired prescribing levels.

Provider Variation in Antibiotic Prescribing and Outcomes of Respiratory Tract Infections.

OBJECTIVES: Inappropriate antibiotic use for respiratory tract infection (RTI) is an ongoing problem linked to the emergence of drug resistance and other adverse effects. Less is known about the prescribing practices of individual physicians or the impact of physician prescribing habits on patient outcomes. We studied the prescribing practices of providers for acute RTIs in an integrated health system, identified patient factors associated with receipt of an antibiotic and assessed the relation between providers' adjusted prescribing rates and a number of patient outcomes. METHODS: This was a retrospective analysis of adults with an RTI visit to any primary care providers across the Cleveland Clinic Health System in 2011-2012. Patients with a history of chronic obstructive pulmonary disease or immunocompromised status were excluded. Logistic regression was used to examine patient factors associated with receipt of an antibiotic. RESULTS: Of 31,416 patients with an RTI, 54.8% received an antibiotic. Patient factors associated with antibiotic prescribing included white race (odds ratio [OR] 1.35, P < 0.001), presence of fever (OR 1.66, P < 0.001), and a diagnosis of bronchitis (OR 10.98, P < 0.001) or sinusitis (OR 33.85, P < 0.001). Among 290 providers with ≥10 RTI visits, adjusted antibiotic prescribing rates ranged from 0% to 100% (mean 49%). Antibiotics were prescribed more often for sinusitis (OR 33.85, P < 0.001), bronchitis (OR 10.98, P < 0.001), or pharyngitis (OR 1.76, P < 0.001) compared with upper respiratory tract infection. Patients who were prescribed antibiotics at the index visit were more likely to return for RTI within 1 year (adjusted OR 1.26, P < 0.001). Emergency department visits for respiratory complications were rare and not associated with antibiotic receipt. CONCLUSIONS: Antibiotic prescribing for RTI varies widely among physicians and cannot be explained by patient factors. Patients prescribed antibiotics for RTI were more likely to return for RTI.

MicroRNA-21 regulates prostaglandin E2 signaling pathway by targeting 15-hydroxyprostaglandin dehydrogenase in tongue squamous cell carcinoma.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) is one of the most aggressive forms of head and neck/oral cancer (HNOC), and is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. Identifying the deregulation of microRNA-mRNA regulatory modules (MRMs) is crucial for understanding the role of microRNA in OTSCC. METHODS: A comprehensive bioinformatics analysis was performed to identify MRMs in HNOC by examining the correlation among differentially expressed microRNA and mRNA profiling datasets and integrating with 12 different sequence-based microRNA target prediction algorithms. Confirmation experiments were performed to further assess the correlation among MRMs using OTSCC patient samples and HNOC cell lines. Functional analyses were performed to validate one of the identified MRMs: miR-21-15-Hydroxyprostaglandin Dehydrogenase (HPGD) regulatory module. RESULTS: Our bioinformatics analysis revealed 53 MRMs that are deregulated in HNOC. Four high confidence MRMs were further defined by confirmation experiments using OTSCC patient samples and HNOC cell lines, including miR-21-HPGD regulatory module. HPGD is a known anti-tumorigenic effecter, and it regulates the tumorigenic actions of Prostaglandin E2 (PGE2) by converts PGE2 to its biologically inactive metabolite. Ectopic transfection of miR-21 reduced the expression of HPGD in OTSCC cell lines, and the direct targeting of the miR-21 to the HPGD mRNA was confirmed using a luciferase reporter gene assay. The PGE2-mediated upregulation of miR-21 was also confirmed which suggested the existence of a positive feed-forward loop that involves miR-21, HPGD and PGE2 in OTSCC cells that contribute to tumorigenesis. CONCLUSIONS: We identified a number of high-confidence MRMs in OTSCC, including miR-21-HPGD regulatory module, which may play an important role in the miR-21-HPGD-PGE2 feed-forward loop that contributes to tumorigenesis.

An alternative technique for hollowing maxillary complete denture.

Extreme resorption of edentulous maxilla may cause difficulty during fabrication of a maxillary complete denture. Increased inter-ridge distance often creates a clinical problem due to heavy-weighted maxillary prosthesis. This article elaborates an alternative approach for hollowing a maxillary complete denture. It utilizes a clear template of the trial denture facilitating the creation of a gelatin cavity form. This hollowing ensures the even thickness of both denture base resins for structural integrity and reduces the heaviness of the denture.

Unique Aspects of Coronary Artery Disease in Indian Women.

PURPOSE: Epidemiologic and clinical research suggests important gender-related differences in the prevalence, presentation, associated conventional and non-conventional risk factors, management and outcomes of coronary heart disease (CHD) patients. Adequate data is not available for Indian population where prevalence of CHD and depression is high. METHOD: We conducted an observational, single-center, study from January 2010 to December 2011 on 10450 consecutive patients visiting a tertiary care center, Ahmedabad, Gujarat, India who presented with complaints related to CHD. RESULTS: Of these, 6867 patients had coronary artery disease (CAD) as confirmed by angiographic investigation; 5678 were males, and 1189 were females with similar mean age. As compared to males, females had higher prevalence of hypertension, diabetes and obesity while males had higher prevalence of smoking. Invasive treatment options like Coronary Artery Bypass Grafting (p < 0.001) and Percutaneous Coronary Intervention (p = 0.001) were used less often to treat females, and medical therapy (p < 0.001) was the preferred treatment option irrespective of the contributing risk factors/extent of CAD. Depression was observed in 39.8% of acute coronary syndrome patients (n = 1648) as assessed by MARDS scale. It was higher in female patients and in low socioeconomic strata (p < 0.001).At 12 and 36 months, rates of revascularization (p < 0.001) and mortality (p < 0.005) were higher with poor quality of life (QoL) (P < 0.001) in depressed CAD patients. CONCLUSION: In India, women appear to have a higher prevalence of hypertension, diabetes, obesity, and family history of CHD. Yet women get invasive treatments less often than men. Depression is also more common in women and is associated with poor QoL and early mortality than men.

Dermatomyositis: Practical Guidance and Unmet Needs.

Dermatomyositis is a heterogeneous idiopathic inflammatory myopathy associated with various cutaneous manifestations and variable presence of myositis, interstitial lung disease, and other visceral organ involvement. An accurate diagnosis of dermatomyositis requires correlating clinical examination findings with serological and histological findings. Familiarity with pathognomonic and common cutaneous manifestations of dermatomyositis, which are highlighted here, can be especially helpful in making an accurate diagnosis. Additionally, evaluating patients for presence of myositis-specific autoantibodies can further support or refute a dermatomyositis diagnosis. When present, myositis-specific autoantibodies can also help guide workups for various dermatomyositis-associated manifestations, as each is associated with relatively distinct clinical characteristics. Evaluating patients for various systemic manifestations often relies on expert opinion recommendations; however, societal guideline statements concerning the evaluation of some manifestations have recently been described. Although malignancy-associated dermatomyositis is a well-accepted subtype, there is limited evidence to support extensive malignancy screening has a favorable benefit-risk ratio in most dermatomyositis patients. However, recent research has uncovered novel associations between dermatomyositis and malignancy, suggesting the possibility of identifying high-risk subsets of dermatomyositis patients in whom malignancy screening may have a high value. Treatment for dermatomyositis has remained largely unchanged over the past several decades. Although many dermatomyositis patients can be effectively treated with current options, either as monotherapy or with combination regimens, there is a need for more targeted and effective DM therapies, in general, and for MDA5(+) dermatomyositis-associated rapidly progressive interstitial lung disease. Fortunately, significant current and emerging research activities evaluating various novel medications for dermatomyositis provide hope for exciting future advances in patients with this intriguing immune-mediated disease.

Intra-abdominal Venous Thromboses and Their Management.

While a plethora of articles discuss management of deep venous thromboses in extremities, there is a relative scarcity of literature comprehensively describing intra-abdominal venous thromboses, and their management. Intra-abdominal venous thromboses include iliocaval venous obstruction (ICVO), hepatic venous thrombosis (HVT), portal venous thrombosis (PVT), renal vein thrombosis (RVT), splenic vein thrombosis (SVT), and gonadal vein thrombosis (GVT); each of which provides unique microenvironmental challenges to management. Doppler ultrasound is the first line imaging modality for diagnosis, and computed tomography and magnetic resonance imaging can help define the extent of thrombus burden and aid with interventional planning. Systemic anticoagulation remains the common medical treatment for intra-abdominal venous thrombosis, however, catheter directed thrombolysis and thrombectomy show positive outcomes in ICVO, HVT, PVT, and RVT, with transjugular intrahepatic portosystemic shunt (TIPS) creation especially beneficial in HVT and PVT. In this review article, we describe pathophysiology, clinical features, imaging findings, and current management options for intra-abdominal venous thromboses.

Link between individual resilience and aggressiveness in dental students and the mediating effect of spirituality: A path analysis.

BACKGROUND: The role of spirituality in people's lives, particularly the lives of health professionals, as well as its impact on mental health issues like anger and aggressiveness and resilience, are particularly significant. Therefore, the purpose of this study was to examine the link between the propensity for violence and personal resilience in dental students by taking into account the function of spirituality as a mediator. MATERIALS AND METHODS: In this cross-sectional questionnaire survey, 211 volunteer dentistry students participated from a government institute in Jammu and Kashmir, India using a stratified sample procedure. The Spiritual Orientation Scale, Buss and Perry Aggression Questionnaire, and Connor-Davidson Resilience Scale were used to gather the data. SPSS version 20.0 was used for conducting a bivariate analysis to ascertain the directionality connection between the research variables. In addition; structural equation modelling analysis was conducted by Smart PLS. RESULTS: According to the findings, resilience and spirituality have a substantial and positive link (r = 0.468 r = 0.023). Aggressiveness and resilience revealed a statistically significant inverse link (r = 0.325, P = 0.04), but aggression and spirituality had no significant correlation. Spirituality played a substantial mediation influence in the indirect pathway of violence on resilience (P = 0.001). CONCLUSION: According to the study's findings, spirituality can help pupils become more resilient as individuals and can act as a helpful intermediary between aggressiveness and resilience.

Diagnosis of Inflammatory Bowel Disease-Associated Peripheral Arthritis: A Systematic Review.

BACKGROUND: Inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA) decreases quality of life and remains poorly understood. Given the prevalence of this condition and its negative impact, it is surprising that evidence-based disease definitions and diagnostic strategies are lacking. This systematic review summarizes available data to facilitate development and validation of diagnostics, patient-reported outcomes, and imaging indices specific to this condition. METHODS: A literature search was conducted. Consensus or classification criteria, case series, cross-sectional studies, cohort studies, and randomized controlled trials related to diagnosis were included. RESULTS: A total of 44 studies reporting data on approximately 1500 patients with pSpA were eligible for analysis. Data quality across studies was only graded as fair to good. Due to large heterogeneity, meta-analysis was not possible. The majority of studies incorporated patient-reported outcomes and a physical examination. A total of 13 studies proposed or validated screening tools, consensus, classification, or consensus criteria. A total of 28 studies assessed the role of laboratory tests, none of which were considered sufficiently accurate for use in diagnosis. A total of 17 studies assessed the role of imaging, with the available literature insufficient to fully endorse any imaging modality as a robust diagnostic tool. CONCLUSIONS: This review highlights existing inconsistency and lack of a clear diagnostic approach for IBD-associated pSpA. Given the absence of an evidence-based approach, a combination of existing criteria and physician assessment should be utilized. To address this issue comprehensively, our future efforts will be directed toward pursuit of a multidisciplinary approach aimed at standardizing evaluation and diagnosis of IBD-associated pSpA.

This systematic review highlights the lack of an evidence-based approach to the diagnosis of inflammatory bowel disease­associated peripheral spondyloarthritis and the need to standardize evaluation and diagnosis via multidisciplinary collaboration with development of patient-reported outcomes and imaging indices.

COVID-19-Induced Encephalopathy: A Case Report.

While COVID-19 is known to cause common neurological manifestations such as loss of taste and smell, headaches, and myalgias, rare and severe neurological complications can also occur. We describe the hospitalization of a middle-aged Caucasian woman who presented with altered mental status and an absence of moderate-severe pulmonary symptoms. The patient tested positive for COVID-19 and experienced a tonic-clonic seizure six days after admission. Diagnostic testing, including cerebrospinal fluid analysis, blood cultures, urine cultures, brain imaging, and electroencephalograms were unremarkable, indicating a global encephalopathic state. This case highlights the need for clinicians to anticipate neurological complications when managing patients with COVID-19, especially when respiratory symptoms are minimal or absent. Moreover, further research on COVID-19-induced encephalopathy is crucial to improve patient outcomes and inform clinical practice.

Navigating the Diagnostic Challenge of Aspergillus Spinal Epidural Abscess in an Immunocompetent Patient: A Case Report and Literature Review.

Aspergillus spinal epidural abscess (ASEA) is a rare, life-threatening condition that can cause spinal cord compression with neurologic deficits. The diagnosis of ASEA can be challenging due to the atypical clinical presentation and low prevalence. We describe the successful management of a rare, immunocompetent, 85-year-old male with ASEA at the T12-L1 and L1-L2 levels and present a review of the literature. Based on most case reports and our knowledge, this is a rare presentation of ASEA in a patient without systemic symptoms, leukocytosis, or a history of immunosuppressive status due to chronic steroid use. The patient presented with multiple falls and lower extremity paraparesis with near-complete paralysis of the right lower extremity for a duration of three months. Systemic symptoms of infection were absent and standard lab evaluations were unremarkable. CT imaging identified cord signal changes at the level of T10-T11 and a contrast block at L1 suspicious for spinal stenosis and impingement. During lumbar spine exploration, purulent fluid consistent with an abscess was found in the epidural space. Cultures were forwarded to microbiology and returned with Aspergillus. Postoperatively, Infectious Disease (ID) recommended treatment with voriconazole, cefepime, and vancomycin, which yielded gradual symptom improvement. The successful management of ASEA requires a multidisciplinary approach involving neurosurgeons, infectious disease specialists, radiologists, and physical therapists. Clinicians should be aware of the possibility of ASEA regardless of systemic symptoms, and early diagnosis and prompt treatment with surgical decompression and appropriate antifungal therapy are imperative for successful management.

Post-COVID Multisystem Inflammatory Syndrome-Adult Leading to Cardiomyopathy and Autoimmune Thyroiditis: A Case Report.

The Coronavirus disease pandemic is an evolving disease with myriad presentations and sequelae. Multisystem inflammatory syndrome in adults (MIS-A) can affect various organ systems, including cardiovascular, gastrointestinal, and neurologic systems, with fever and abnormally increased inflammatory markers without significant respiratory affection. This is a well-known complication in children (MIS-C). Validated clinical criteria are used to diagnose this condition. Long-term sequelae of MIS-A are unclear and underreported. Here, we describe a case of Post-COVID-19 MIS-A who presented with cardiac dysfunction, hepatitis, and acute kidney injury and recovered well with steroids. He was left with persistent cardiomyopathy and thyroiditis with hypothyroidism which to date has not fully recovered. This case emphasizes that the sequelae of COVID-19 and its pathophysiology are not fully understood, and more research is needed to predict and prevent the same.

A novel 3-miRNA network regulates tumour progression in oral squamous cell carcinoma.

BACKGROUND: Late diagnosis is one of the major confounders in oral squamous cell carcinoma (OSCC). Despite recent advances in molecular diagnostics, no disease-specific biomarkers are clinically available for early risk prediction of OSCC. Therefore, it is important to identify robust biomarkers that are detectable using non-invasive liquid biopsy techniques to facilitate the early diagnosis of oral cancer. This study identified potential salivary exosome-derived miRNA biomarkers and crucial miRNA-mRNA networks/underlying mechanisms responsible for OSCC progression. METHODS: Small RNASeq (n = 23) was performed in order to identify potential miRNA biomarkers in both tissue and salivary exosomes derived from OSCC patients. Further, integrated analysis of The Cancer Genome Atlas (TCGA) datasets (n = 114), qPCR validation on larger patient cohorts (n = 70) and statistical analysis with various clinicopathological parameters was conducted to assess the effectiveness of the identified miRNA signature. miRNA-mRNA networks and pathway analysis was conducted by integrating the transcriptome sequencing and TCGA data. The OECM-1 cell line was transfected with the identified miRNA signature in order to observe its effect on various functional mechanisms such as cell proliferation, cell cycle, apoptosis, invasive as well as migratory potential and the downstream signaling pathways regulated by these miRNA-mRNA networks. RESULTS: Small RNASeq and TCGA data identified 12 differentially expressed miRNAs in OSCC patients compared to controls. On validating these findings in a larger cohort of patients, miR-140-5p, miR-143-5p, and miR-145-5p were found to be significantly downregulated. This 3-miRNA signature demonstrated higher efficacy in predicting disease progression and clinically correlated with poor prognosis (p < 0.05). Transcriptome, TCGA, and miRNA-mRNA network analysis identified HIF1a, CDH1, CD44, EGFR, and CCND1 as hub genes regulated by the miRNA signature. Further, transfection-mediated upregulation of the 3-miRNA signature significantly decreased cell proliferation, induced apoptosis, resulted in G2/M phase cell cycle arrest and reduced the invasive and migratory potential by reversing the EMT process in the OECM-1 cell line. CONCLUSIONS: Thus, this study identifies a 3-miRNA signature that can be utilized as a potential biomarker for predicting disease progression of OSCC and uncovers the underlying mechanisms responsible for converting a normal epithelial cell into a malignant phenotype.

An unusual arrangement between the highest denticulate ligament and posterior inferior cerebellar artery.

The posterior inferior cerebellar artery (PICA) is often involved in pathologies of the posterior cranial fossa. Therefore, a good understanding of the vessel's normal and variant courses is important to the neurosurgeon or neurointerventionalist. During the routine microdissection of the craniocervical junction, an unusual arrangement between the highest denticulate ligament and PICA was observed. On the right side, the PICA was given rise to by the V4 segment of the vertebral artery 9 mm after the artery entered the dura mater of the posterior cranial fossa. The artery made an acute turn around the lateral edge of the highest denticulate ligament to then recur 180 degrees and travel medially toward the brainstem. Invasive procedures that target the PICA should be aware of the variant as described herein.

Human CD4 cytotoxic T lymphocytes mediate potent tumor control in humanized immune system mice.

Efficacy of immune checkpoint inhibitors in cancers can be limited by CD8 T cell dysfunction or HLA-I down-regulation. Tumor control mechanisms independent of CD8/HLA-I axis would overcome these limitations. Here, we report potent CD4 T cell-mediated tumor regression and memory responses in humanized immune system (HIS) mice implanted with HT-29 colorectal tumors. The regressing tumors showed increased CD4 cytotoxic T lymphocyte (CTL) infiltration and enhanced tumor HLA-II expression compared to progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating tumor clearance independent of CD8 T cells and provides a platform to study human anti-tumor immunity in vivo.