Expression and function of VISTA on myeloid cells.

V-domain containing Ig Suppressor of T cell Activation (VISTA) is predominantly expressed on myeloid cells and functions as a ligand/receptor/soluble molecule. In inflammatory responses and immune responses, VISTA regulates multiple functions of myeloid cells, such as chemotaxis, phagocytosis, T cell activation. Since inflammation and immune responses are critical in many diseases, VISTA is a promising therapeutic target. In this review, we will describe the expression and function of VISTA on different myeloid cells, including neutrophils, monocytes, macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs). In addition, we will discuss whether the functions of VISTA on these cells impact the disease processing.

Triptolide enhances carboplatin-induced apoptosis by inhibiting nucleotide excision repair (NER) activity in melanoma.

Introduction: Carboplatin (CBP) is a DNA damaging drug used to treat various cancers, including advanced melanoma. Yet we still face low response rates and short survival due to resistance. Triptolide (TPL) is considered to have multifunctional antitumor effects and has been confirmed to enhance the cytotoxic effects of chemotherapeutic drugs. Herein, we aimed to investigate the knowledge about the effects and mechanisms for the combined application of TPL and CBP against melanoma. Methods: Melanoma cell lines and xenograft mouse model were used to uncover the antitumor effects and the underlying molecular mechanisms of the alone or combined treatment of TPL and CBP in melanoma. Cell viability, migration, invasion, apoptosis, and DNA damage were detected by conventional methods. The rate-limiting proteins of the NER pathway were quantitated using PCR and Western blot. Fluorescent reporter plasmids were used to test the NER repair capacity. Results: Our results showed that the presence of TPL in CBP treatment could selectively inhibit NER pathway activity, and TPL exerts a synergistic effect with CBP to inhibit viability, migration, invasion, and induce apoptosis of A375 and B16 cells. Moreover, combined treatment with TPL and CBP significantly inhibited tumor progression in nude mice by suppressing cell proliferation and inducing apoptosis. Discussion: This study reveals the NER inhibitor TPL which has great potential in treating melanoma, either alone or in combination with CBP.

Chemotherapy induces immune checkpoint VISTA expression in tumor cells via HIF-2alpha.

Tumor cells can evade the innate and adaptive immune systems, which play important roles in tumor recurrence and metastasis. Malignant tumors that recur after chemotherapy are more aggressiveciscis, suggesting an increased ability of the surviving tumor cells to evade innate and adaptive immunity. Therefore, in order to reduce patient mortality, it is important to discover the mechanisms by which tumor cells develop resistance to chemotherapeutics. In the present study we focused on the tumor cells that survived chemotherapy. We found that chemotherapy could promote the expression of VISTA in tumor cells, and that this change was mediated by HIF-2α. In addition, VISTA overexpression on melanoma cells promoted immune evasion, and the application of the VISTA-blocking antibody 13F3 enhanced the therapeutic effect of carboplatin. These results offer an insight into the immune evasion of chemotherapy-resistant tumors, and provide a theoretical basis for the combined application of chemotherapy drugs and VISTA inhibitors to treat tumors.

Recent advances in enterovirus A71 pathogenesis: a focus on fatal human enterovirus A71 infection.

Enterovirus A71 (EV-A71) is one of the major pathogens responsible for hand, foot, and mouth disease (HFMD). Many HFMD outbreaks have been reported throughout the world in the past decades. Compared with other viruses, EV-A71 infection is more frequently associated with severe neurological complications and even death in children. EV-A71 can also infect adults and cause severe complications and death, although such cases are very uncommon. Although fatal cases of EV-A71 infection have been reported, the underlying mechanisms of EV-A71 infection, especially the mode of viral spread into the central nervous system (CNS) and mechanisms of pulmonary edema, which is considered to be the direct cause of death, have not yet been fully clarified, and more studies are needed. Here, we first summarize the pathological findings in various systems of patients with fatal EV-A71 infections, focussing in detail on gross changes, histopathological examination, tissue distribution of viral antigens and nucleic acids, systemic inflammatory cell infiltration, and tissue distribution of viral receptors and their co-localization with viral antigens. We then present our conclusions about viral dissemination, neuropathogenesis, and the mechanism of pulmonary edema in EV-A71 infection, based on pathological findings.

Development and Validation of a Mutational Burden-Associated LncRNA Signature for Improving the Clinical Outcome of Hepatocellular Carcinoma.

BACKGROUND: Long non-coding RNAs (lncRNAs) modulate numerous cellular processes, including DNA damage repair. Here, we investigated the clinical importance of lncRNAs associated with mutational burden in hepatocellular carcinoma (HCC). METHODS: Prognosis-related lncRNAs associated with mutational burden were screened and determined to score the mutational burden-associated lncRNA signature (MbLncSig) from TCGA. Prognostic values and predictive performance of the MbLncSig score were analysed. RESULTS: Four mutational burden-associated lncRNAs (AC010643.1, AC116351.1, LUCAT1 and MIR210HG) were identified for establishing the MbLncSig score. The MbLncSig score served as an independent risk factor for HCC prognosis in different subgroup patients. The predictive performance of one-year and three-year OS was 0.739 and 0.689 in the entire cohort, respectively. Moreover, the MbLncSig score can further stratify the patient survival in those with TP53 wild type or mutation. CONCLUSIONS: This study identified a four-lncRNA signature (the MbLncSig score) which could predict survival in HCC patient with/without TP53 mutation.

Pathologic and molecular studies of enterovirus 71 infection in a fatal case from a recent epidemic in China: A case report.

RATIONALE: Enterovirus 71 (EV71) is identified as the primary cause of hand, foot, and mouth disease (HFMD) and mainly infects the young infants. Though some fatal cases have been reported, the underlying mechanisms of EV71 infection remain elusive and more further pathologic and molecular studies of EV71 infection are needed. PATIENT CONCERNS: A 26-month-old girl with a history of fever and lethargy for 3 days and intermittent seizures for 2 hours associated with rash on 4 limbs was brought to a hospital. DIAGNOSES: The autopsy was performed to identify the cause of death for a medical dispute. The results of histologic examination, immunohistochemistry (IHC), nested reverse transcription polymerase chain reaction (RT-PCR), and viral isolation confirmed that this patient died of EV71 infection. INTERVENTIONS: The patient was transferred to neonatal intensive care unit and was intubated and mechanically ventilated. The other treatment included cardiopulmonary resuscitation and intravenous injection of adrenaline. OUTCOMES: The patient presented persistent coma and intermittent seizures and suddenly developed respiratory arrest and died 16 hours after admission. LESSONS: Our results suggest that EV71 might invade into the central nervous system (CNS) through peripheral nerves which control the digestive tract in the early stage of infection. In addition, we successfully isolated one EV71 strain. Phylogenetic analysis showed that the isolated strain clustered in the C4a of C4 subgenotype. This case also highlights that rapid deterioration in HFMD cases is still a challenge to physicians and they must pay special attention to the infants with HFMD symptoms, particularly in EV71 epidemic areas for early diagnosis and treatment.

Sudden death in a patient with severe mitral annular calcification and end-stage renal disease during hemodialysis: A case report.

RATIONALE: Mitral annular calcification (MAC) is a chronic, degenerative cardiac condition. Although MAC is often considered as an incidental finding in clinical and forensic practice, sudden death due to severe MAC with end-stage renal disease (ESRD) during hemodialysis is uncommon. In addition, spontaneous subepicardial hematoma due to rupture of the subepicardial vein is very rare. PATIENT CONCERNS: A 65-year-old woman had a history of hypertension, diabetes mellitus, and renal failure. DIAGNOSES: Postmortem examination revealed marked MAC with cardiomegaly and ESRD. Spontaneous subepicardial hematoma due to disruption of subepicardial vein was also seen. INTERVENTIONS AND OUTCOMES: The patient became short of breath while on hemodialysis and expired en route to the hospital. LESSONS: In this case, death was attributed to the effects of the calcified mitral valve annulus. This case highlights that MAC must be considered in any patient with ESRD and fatal cardiovascular events should not be overlooked in these patients.

Pathologic Studies of Fatal Encephalomyelitis in Children Caused by Enterovirus 71.

OBJECTIVES: Enterovirus 71 (EV71) is the major pathogen of hand, foot, and mouth disease and can cause death; however, its pathogenesis remains elusive. METHODS: We performed a detailed systematic histopathologic examination and molecular studies on six autopsy cases of EV71 infection using H&E, immunohistochemistry, double immunofluorescence staining, and nested reverse transcription polymerase chain reaction. RESULTS: Characteristic features of acute encephalomyelitis were observed. Viral antigens were mainly detected in neuronal cytoplasm and processes in the different brainstem nuclei and spinal cord, including the anterior and posterior horn cells. Viral antigens were also positive in the nerve roots of spinal cord and autonomic ganglia of intestines. CONCLUSIONS: Our study revealed direct pathologic evidence supporting viral entry into the central nervous system (CNS) through peripheral nerves. In addition to the major motor pathway, EV71 can also enter the CNS via peripheral sensory and autonomic pathways in retrograde axonal transport.

Three homicides with darts tainted with succinylcholine: autopsy and toxicology.

In emergency departments, intoxication with the muscle relaxant succinylcholine (SUX) often leads to a potentially lethal respiratory paralysis or other deleterious side effects. However, homicide cases with SUX poisoning are very rare because the toxic or lethal concentration ranges of SUX have not yet been determined. We described three uncommon homicide cases due to acute poisoning by darts contaminated with SUX. All the victims died quickly (less than 30 min) after being shot by an especially designed dart gun. Succinylmonocholine (SMC), a metabolite of SUX, was used as a marker to detect the latter. HPLC-MS/MS analysis demonstrated the presence of SUX in the droplet residues of the darts and SMC in the blood and urine in all cases. SMC concentrations of 0.45, 14.0, and 17.9 ng/ml were detected in the victims' blood and 259.0 ng/ml in the urine from the third case. The main pathological changes consisted of hemorrhage of the injured soft tissues, visceral congestion, severe pulmonary edema, and multifocal petechial hemorrhage of the heart and lungs. Taken together, the findings supported a diagnosis of fatal SUX poisoning. Futhermore, our study provided a reference for the lethal concentrations of SUX poisoning.

Human fatality due to thallium poisoning: autopsy, microscopy, and mass spectrometry assays.

Thallium has been responsible for many intoxications since its discovery; however, toxicological profiles for thallium in human fatalities have not been updated recently. Autopsy, microscopic investigations, and toxicological analyses were performed on a married couple who died from thallium sulfate intended homicidal poisoning. The distribution of thallium was established by inductively coupled plasma mass spectrometry with hair samples showing the highest thallium concentration. Electron microscopy revealed a dystrophic condition of hair with disorganized cuticle and atrophy of the hair bulb. Thallium interacts with cells at different levels, with prominent ultrastructural injuries in the mitochondria and endoplasmic reticulum, and high concentration of electron dense granules observed in the cytoplasm and mitochondria of several organs. Alopecia, toxic encephalopathy, and peripheral neuropathy were diagnosed in the victims and suggested to be crucial implications for thallium poisoning. The analytical procedures used in this case are of considerable forensic importance in the diagnosis of thallium poisoning.

Fatal delayed cardiac tamponade due to rupture of micropseudoaneurysm of left anterior descending coronary artery following stab to the chest.

Traumatic coronary pseudoaneurysm has been described to be mainly associated to iatrogenic lesion of the coronary arteries. However, chest-stab-wound-related coronary pseudoaneurysm caused by isolated partial incision of a coronary artery giving rise to fatal delayed cardiac tamponade is very rare. We describe an autopsy case in which this potentially fatal complication developed 8 days later after a thoracic stab wound. Unfortunately, the imaging examination failed to detect this defect during hospitalization. Postmortem examination revealed that the posterior wall of the left anterior descending coronary artery was intact but that the anterior wall was incised, forming a micropseudoaneurysm which had ruptured. This case highlights that isolated coronary artery injuries must be considered in any patient with a penetrating wound to the thorax, and coronary pseudoaneurysms should not be missed in these patients.

Polyacrylamide hydrogel pulmonary embolism--A fatal consequence of an illegal cosmetic vaginal tightening procedure: A case report.

Vaginal tightening is a kind of esthetic surgery aimed at enhancing sexual satisfaction during intercourse. Although the injective vaginal tightening procedure is informal, there are already some reports of its application. But pulmonary embolism is a really rare therapeutic complication of this procedure. We report a case of death due to the non-thrombotic pulmonary embolism as a consequence of illegal cosmetic vaginal-tightening procedure using polyacrylamide hydrogel. A 34-year-old woman was hospitalized with paroxysmal abdominal cramps and diarrhea as initial symptoms, while she concealed the genital cosmetic surgery history. Respiratory distress presented only 1.5h before she died. The result of autopsy revealed the cause of death as pulmonary embolism due to the hydrogel which was injected into her vaginal wall. The emboli were confirmed as polyacrylamide hydrogel by Alcian-blue stain and the Fourier transform infrared scanning. It is suggested that pulmonary embolism should not be discarded in the expertise of deaths following cosmetic implant surgeries. It broadens our understanding about death associated with esthetic genital procedures and informs clinicians and medical examiners of the potential death of this type. And detailed investigations of previous medical and surgical history will always play a critical role in the certification of cause of death.

Temporal profiles of axonal injury following impact acceleration traumatic brain injury in rats--a comparative study with diffusion tensor imaging and morphological analysis.

Traumatic axonal injury (TAI) plays a major role in the development of neurological impairments after traumatic brain injury (TBI), but it is commonly difficult to evaluate it precisely and early with conventional histological biomarkers, especially when the patients experience short-term survival after TBI. Diffusion tensor imaging (DTI) has shown some promise in detecting TAI, but longitudinal studies on the compromised white matter with DTI at early time points (≤72 h) following impact acceleration TBI are still absent. In the present study, rats were subjected to the Marmarou model and imaged with DTI at 3, 12, 24, and 72 h (n = 5 each) post-injury. Using a region-of-interest-based approach, the regions of interest including the corpus callosum, bilateral external capsule, internal capsule, and pyramidal tract were studied. Two DTI parameters, fraction anisotropy and axial diffusivity, were significantly reduced from 3 to 72 h in each region after trauma, corresponding to the gradient of axonal damage demonstrated by immunohistochemical staining of ß-amyloid precursor protein and neurofilament light chain. Remarkably, DTI changes predicted the approximate time in the acute phase following TBI. These results indicate that the temporal profiles of diffusion parameters in DTI may be able to provide a tool for early diagnosis of TAI following impact acceleration TBI.

[Magnetic resonance diffusion tensor imaging for diagnosis of pyramidal tract damage in rats].

OBJECTIVE: To explore the applicability of magnetic resonance diffusion tensor imaging (DTI) for diagnosis of pyramidal tract damage in rats. METHODS: Marmarou's model was set up, followed by DTI scanning at 3, 12, 24 and 72 h post trauma to acquire the dispersion parameter of bilateral pyramidal tracts. Moreover, axonal varicosities per square millimeter and the percentage of positive area of axons demonstrated by beta-amyloid precursor protein (beta-APP) immunostaining were obtained, as well as the mean density and sum density of neurofilament (NF) 68 immunostaining. RESULTS: Axial diffusivity (AD), fraction anisotropy (FA) and relative anisotropy (RA) in the pyramidal tract were significantly and continuously reduced and reached to the bottom at 72h post trauma (P < 0.05) in accord with the gradient of axonal damage verified by beta-APP and NF68 immunostaining. Furthermore, the changes of AD, FA and RA showed a significant negative correlation with the beta-APP immunohistochemical results. CONCLUSION: DTI has important value for early diagnosis in pyramidal tract damage.

[Advance in animal models of traumatic brain injury].

Traumatic brain injury (TBI) is a highly complex multi-factorial disorder. Animal models of TBI are used to elucidate primary and secondary injury mechanisms and pathophysiological changes and to provide the diagnostic and therapeutical basis for TBI. The choices of animal models depend upon the research objectives. However, various animal models have limitations. The models only can duplicate the pivotal injury mechanisms or a certain important pathophysiological course. The characteristics of human TBI can not fully be reflected by using these models. In the review, animal models of traumatic brain injury are classified as dynamic direct brain injury, indirect dynamic brain injury and combined neuro-traumatic models. Several common models are described for consideration.