Association of differential expression of immunoregulatory molecules and presence of targetable mutations may inform rational design of clinical trials.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and genomic biomarker-driven targeted therapies have revolutionized the modern oncologic treatment arsenal. The next step has been to combine targeted agents and ICIs. In doing so, some combination regimens may be more logical than others. PATIENTS AND METHODS: Whole-exome and whole-transcriptome sequencing were performed on 2739 unselected later-stage clinical cases from 24 solid tumor subtypes in the NantHealth database, and data were also curated from 5746 similarly sequenced patients across 28 solid tumor subtypes in The Cancer Genome Atlas (TCGA). Significant differential expression of 10 immunoregulatory molecules [IRMs (genes)] was analyzed for association with mutant versus wild-type genes. RESULTS: Twenty-three significant associations between currently actionable variants and RNA-expressed checkpoint genes were identified in the TCGA cases; 10 were validated in the external cohort of 2739 clinical cases from NantHealth (P values were adjusted using Benjamini-Hochberg multiple hypothesis correction to reduce false-discovery rate). Within the same 5746 TCGA profiles, 2740 TCGA patients were identified as having one or more potentially oncogenic single-nucleotide variant (SNV) mutation within an established 50-gene hotspot panel. Of the 50 genes, SNVs within 15 were found to be significantly associated with differential expression of at least one IRM after adjusting for tissue enrichment; six were confirmed significant associations in an independent set of 2739 clinical cases from NantHealth. CONCLUSIONS: Logically combining ICIs with targeted therapies may offer unique treatment strategies for patients with cancer. The presence of specific mutations impacts the expression of IRMs, an observation of potential importance for selecting combinations of gene- and immune-targeted therapeutics.

Strain and damage-sensing performance of biocompatible smart CNT/UHMWPE nanocomposites.

Herein, we report strain- and damage-sensing performance of biocompatible smart CNT/UHMWPE nanocomposites for the first time. CNT/UHMWPE nanocomposites are fabricated by solution mixing followed by compression molding. The surface morphology, microstructural properties, thermal decomposition and stability, glass transition temperature and thermal conductivity of the nanocomposites are characterized. The degree of crystallinity of CNT/UHMWPE nanocomposites is found to have a maximum value of 52% at 0.1 wt% CNT loading. The degree of crystallinity influences the mechanical properties of the CNT/UHMWPE nanocomposites. The electrical percolation threshold is achieved at 0.05 wt% of CNT and it follows a two dimensional conductive network according to percolation theory. The piezoresistive response of CNT/UHMWPE nanocomposites is demonstrated with a gauge factor of ~2.0 in linear elastic regime and that in the range of 3.8-96.0 in inelastic regimes for 0.05 wt% of CNT loading. A simple theoretical model is also developed to predict the resistivity evolution in both elastic and inelastic regimes. High sensitivity of CNT/UHMWPE nanocomposites coupled with linear piezoresistive response up to 100% strain demonstrates their potential for application in artificial implants as a self-sensing material.

A two centre observational study of simultaneous pulse oximetry and arterial oxygen saturation recordings in intensive care unit patients.

The influence of variables that might affect the accuracy of pulse oximetry (SpO2) recordings in critically ill patients is not well established. We sought to describe the relationship between paired SpO2/SaO2 (oxygen saturation via arterial blood gas analysis) in adult intensive care unit (ICU) patients and to describe the diagnostic performance of SpO2 in detecting low SaO2 and PaO2. A paired SpO2/SaO2 measurement was obtained from 404 adults in ICU. Measurements were used to calculate bias, precision, and limits of agreement. Associations between bias and variables including vasopressor and inotrope use, capillary refill time, hand temperature, pulse pressure, body temperature, oximeter model, and skin colour were estimated. There was no overall statistically significant bias in paired SpO2/SaO2 measurements; observed limits of agreement were +/-4.4%. However, body temperature, oximeter model, and skin colour, were statistically significantly associated with the degree of bias. SpO2 <89% had a sensitivity of 3/7 (42.9%; 95% confidence intervals, CI, 9.9% to 81.6%) and a specificity of 344/384 (89.6%; 95% CI 86.1% to 92.5%) for detecting SaO2 <89%. The absence of statistically significant bias in paired SpO2/SaO2 in adult ICU patients provides support for the use of pulse oximetry to titrate oxygen therapy. However, SpO2 recordings alone should be used cautiously when SaO2 recordings of 4.4% higher or lower than the observed SpO2 would be of concern. A range of variables relevant to the critically ill had little or no effect on bias.

Autonomic symptom burden is associated with MS-related fatigue and quality of life.

BACKGROUND: Nonspecific symptoms such as fatigue and dizziness are common in multiple sclerosis (MS), even in patients with normal exams. Little is known about the relationship of autonomic dysfunction with these symptoms and quality of life. OBJECTIVE: Assess the association of autonomic symptom burden with fatigue, clinical status and quality of life. METHODS: Subjects completed an autonomic symptom (COMPASS-31), quality of life (MSQOL-54) and fatigue (FSS) questionnaire at their routine MS clinic follow-up. Demographic and clinical data were collected from the medical record. Pearson correlations were assessed between autonomic symptoms and fatigue, quality of life, disability and disease duration. RESULTS: One-hundred subjects completed the study (mean age 48 years; 78% female; 84% relapsing-remitting), mean disease duration was 14.7 years and mean EDSS 2.5. MSQOL-54 composite scores were 58 physical and 65 mental. COMPASS-31 correlated with MSQOL-54 (Physical R= -0.60; Mental -0.54; p<0.001) and FSS (R=0.51; p<0.001). There was no relationship between COMPASS-31 and EDSS (R=0, p=0.97) or disease duration (R= -0.02, p=0.84). CONCLUSIONS: Autonomic symptom burden is correlated with decreased quality of life and increased fatigue. Autonomic symptoms are present early in the disease and at low disability and may reflect aspects of disease burden that are not well-captured by current disability measures.

Comparative evaluation of chlorhexidine varnish and fluoride varnish on plaque Streptococcus mutans count--an in vivo study.

AIM: The aim of the study was to assess and compare the effect of chlorhexidine varnish and fluoride varnish application on Streptococcus mutans counts in plaque of occlusal pits and fissures of permanent mandibular first molars. MATERIALS AND METHODS: The study was an in vivo comparative study, conducted among 50 schoolchildren aged 7-8 years under a field setting. The 50 subjects were randomly allocated into two groups. Baseline plaque samples were collected from all the subjects followed by the application of two varnishes, Cervitec and Duraphat. The varnish was applied to pit and fissures of occlusal surface of mandibular first molar. The varnish application was carried out on the first day, fifth day and tenth day after baseline plaque sampling. Subsequent plaque samples were collected at the end of 1 month and at the end of 3 months after the varnish application. RESULTS: The Cervitec varnish has shown a statistically significant reduction at the end of 1 month and at the end of 3 months (P < 0.05). Duraphat varnish did not show a statistically significant difference in reducing the plaque S. mutans count at the end of 1 month and third month (P > 0.05). CONCLUSION: Cervitec varnish was found to be effective in reducing S. mutans count for a 3-month period, when compared to Duraphat varnish.

Laparoscopic major hepatectomy: pure laparoscopic approach versus hand-assisted technique.

Laparoscopic liver resections are being performed with increasing frequency, with several groups having reported minimally invasive approaches for major anatomic hepatic resections. Some surgeons favor a pure laparoscopic approach, while others prefer a hand-assisted approach for major laparoscopic liver resections. There are clear advantages and disadvantages to a hand-assisted technique. The purpose of this study is to summarize the literature comparing pure laparoscopic and hand-assisted approaches for minimally invasive hepatic resection, and to describe our approach in 432 laparoscopic liver resections.

Low frequency vibrational modes of room temperature ionic liquids.

The vibrational spectra of four ionic liquids, sharing the same imidazolium cation but containing different anions-[bmim][NO(3)], [bmim][BF(4)], [bmim][PF(6)], and [bmim][NTf(2)]-have been obtained using normal-mode analysis within the harmonic approximation and from velocity autocorrelation functions from a molecular dynamics trajectory generated using empirical force fields. The vibrational density of states obtained from the two methods agree well. The low frequency modes (<100 cm(-1)) exhibit a red shift with an increase in the anion size. Deuteration of the ring hydrogens leads to a negligible change in this region of the spectrum. The participation ratio of low frequency modes is large, implying that they are not localized to a few atoms. The low frequency band arises primarily from short-range interionic interactions, and the exact peak position is modulated by the cation-anion hydrogen bond strength. Results obtained from these force-field-based calculations are confirmed by ab initio molecular dynamics simulations of crystalline [bmim][PF(6)].

Orthodontic uprighting of impacted mandibular permanent second molar: a case report.

The mandibular second molars can become impacted beneath the crown of the first molars due to various causes and fail to erupt normally. Presented herewith is a case report of orthodontic uprighting of a mesioangular impacted mandibular right permanent second molar. Though various treatment options were available, an uprighting push spring appliance was used as it is easy to fabricate and produces distal tipping and uprighting of the impacted tooth without the necessity of surgical assistance, bone removal, or splinting. The uprighting of the mandibular second molar was achieved within two months.

Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation.

Eukaryotic cells rely on a surveillance mechanism known as the spindle checkpoint to ensure accurate chromosome segregation. The spindle checkpoint prevents sister chromatids from separating until all kinetochores achieve bipolar attachments to the mitotic spindle. Checkpoint proteins tightly inhibit the anaphase-promoting complex (APC), a ubiquitin ligase required for chromosome segregation and progression to anaphase. Unattached kinetochores promote the binding of checkpoint proteins Mad2 and BubR1 to the APC-activator Cdc20, rendering it unable to activate APC. Once all kinetochores are properly attached, however, cells inactivate the checkpoint within minutes, allowing for the rapid and synchronous segregation of chromosomes. How cells switch from strong APC inhibition before kinetochore attachment to rapid APC activation once attachment is complete remains a mystery. Here we show that checkpoint inactivation is an energy-consuming process involving APC-dependent multi-ubiquitination. Multi-ubiquitination by APC leads to the dissociation of Mad2 and BubR1 from Cdc20, a process that is reversed by a Cdc20-directed de-ubiquitinating enzyme. The mutual regulation between checkpoint proteins and APC leaves the cell poised for rapid checkpoint inactivation and ensures that chromosome segregation promptly follows the completion of kinetochore attachment. In addition, our results suggest a mechanistic basis for how cancer cells can have a compromised spindle checkpoint without corresponding mutations in checkpoint genes.

The contralateral slip. An avoidable complication and indication for prophylactic pinning in slipped upper femoral epiphysis.

Between July 1994 and June 2004, 60 patients with 76 slipped upper femoral epiphyses were managed within the adult trauma service of three hospitals. Treatment was by a single cannulated screw. Of these cases, 53 were unilateral, in 17 of which uncomplicated prophylactic fixation of the contralateral hip was performed. Of the other 36 cases, nine presented with a subsequent slip despite ongoing out-patient care. The subsequent slip was unpredictable in timing and unrelated to the age at the initial slip. It was more often unstable and in one case avascular necrosis developed. The overall rate of avascular necrosis, although in accordance with the literature, was 60% in acute unstable slips with a slip angle greater than 40 degrees. In our experience, prophylactic fixation was safer than continued observation of the contralateral hip.

Chronic ethanol and nicotine interaction on rat tissue antioxidant defense system.

Ethanol consumption and cigarette smoking are common in societies worldwide and have been identified as injurious to human health. This study was undertaken to examine the interactive effects of chronic ethanol and nicotine consumption on the antioxidant defense system in different tissues of rat. Male Fisher-344 rats were divided into four groups of five animals each and treated for 6.5 weeks as follows: (1) Control rats were administered normal saline orally; (2) ethanol (20% [wt./vol.]) was given orally at a dose of 2 g/kg; (3) nicotine was administered subcutaneously at a dose of 0.1 mg/kg; and (4) a combination of ethanol plus nicotine was administered by the route and at the dose described above. The animals were killed 20 h after the last treatment, and liver, lung, kidney, and testes were isolated and analyzed. Chronic ingestion of ethanol resulted in a significant depletion of glutathione (GSH) content in liver, lung, and testes, whereas chronic administration of nicotine significantly depleted GSH content in liver and testes. The combination of ethanol plus nicotine resulted in a significant depletion of GSH content in liver, lung, and testes. Ethanol, nicotine, or a combination of ethanol plus nicotine significantly increased superoxide dismutase (SOD) activity in liver and decreased SOD activity in kidney. Ethanol, nicotine, or a combination of ethanol plus nicotine significantly decreased catalase (CAT) activity in liver and increased CAT activity in kidney and testes. Chronic ingestion of ethanol resulted in a significant decrease in glutathione peroxidase (GSH-Px) activity in liver and kidney, whereas a combination of ethanol plus nicotine increased GSH-Px activity in liver and decreased GSH-Px activity in kidney and testes. Ethanol, nicotine, or a combination of ethanol plus nicotine significantly increased lipid peroxidation, respectively, in liver. It is suggested that prolonged exposure to ethanol and nicotine produce similar, and in some cases additive, oxidative tissue injuries in rat.

Autoantibodies to IA-2 and GAD65 in patients with type 2 diabetes mellitus of varied duration: prevalence and correlation with clinical features.

OBJECTIVE: To determine the prevalence of autoantibodies to IA-2 (IA-2Ab) and glutamic acid decarboxylase (GADAb) in type 2 diabetes, their relationship to disease duration, and their importance in management decisions. METHODS: We undertook a study of 101 patients with type 2 diabetes (defined as nonketotic hyperglycemia at diagnosis) of varied duration (median, 4 years). Results were compared with those from 36 patients with type 1 diabetes also of varied duration (median, 2 years). IA-2Ab and GADAb were measured by radioligand-binding assays with use of in vitro-synthesized, 35S-labeled antigens. RESULTS: Of the 101 patients with type 2 diabetes, 20 (20%) were positive for GADAb; only 4 of these 20 were positive for IA-2Ab. In comparison, 75% of patients with type 1 diabetes were positive for GADAb, IA-2Ab, or both (P<0.0001). The coincidence of IA-2Ab positivity in GADAb-positive patients with type 2 diabetes was significantly lower than in patients with type 1 diabetes (20% versus 73%, respectively; P = 0.002). All four IA-2Ab- and GADAb-positive patients with type 2 diabetes required insulin and were younger than those positive for GADAb alone (P = 0.018). GADAb positivity in patients with type 2 diabetes was highly associated with insulin requirement (P = 0.004), with an odds ratio of 5.8 in predicting insulin dependence. Among patients with type 2 diabetes receiving insulin therapy, disease duration was significantly shorter (P = 0.025) and body mass index was significantly lower (P<0.001) in GADAb-positive versus GADAb-negative patients. In contrast to type 1 diabetes, in which GADAb values were negatively correlated with disease duration (r = -0.34; P = 0.044), no significant correlation with disease duration was observed in type 2 diabetes (r = -0.166; P = 0.48). CONCLUSION: Irrespective of duration of disease, measurement of IA-2Ab and GADAb can help to identify those patients with type 2 diabetes most likely to require insulin therapy.

The utility of urgent colonoscopy in the evaluation of acute lower gastrointestinal tract bleeding: a 2-year experience from a single center.

OBJECTIVE: Urgent colonoscopy is often recommended to evaluate acute rectal bleeding. However, it may not identify a source because of blood in the lumen or inadequate preparation. Our aim was to determine the utility of urgent colonoscopy as the initial test for acute rectal bleeding. METHODS: This was a retrospective chart review of all patients discharged in 1997 and 1998 with an International Classification of Diseases, 9th Revision, code for hematochezia or rectal bleeding. RESULTS: We identified 514 charts but excluded 424 because of inaccurate coding. In the 90 with confirmed acute rectal bleeding, colonoscopy was the initial test in 39; age, sex, and race distributions were similar to those who did not have colonoscopy. A definite source of bleeding was seen at colonoscopy in only three patients, a probable source in 26, and no source in 10. Therapeutic intervention in four patients with a definite or probable source was successful in three. The commonest reasons for not performing urgent colonoscopy were bleeding from presumed hemorrhoids or bleeding that was clinically insignificant. Spontaneous resolution of bleeding and length of hospital stay were not affected by urgent colonoscopy. Five patients had surgery for unrelated reasons. In-hospital mortality was 2% and was unrelated to bleeding. CONCLUSION: Urgent colonoscopy as the initial investigation in acute lower GI tract bleeding probably does not alter the outcome in most cases. Identification of a definite bleeding source leading to successful therapeutic intervention is rare. Spontaneous resolution is frequent, length of hospital stay is similar, and clinical outcome is excellent regardless of whether or not urgent colonoscopy is performed.

Eukaryotic-like adenylyl cyclases in Mycobacterium tuberculosis H37Rv: cloning and characterization.

Screening the Mycobacterium tuberculosis H37Rv genomic library for complementation of catabolic defect for cAMP-dependent expression of maltose operon produced the adenylyl cyclase gene (Mtb cya, (1997)) annotated later as Rv1625c (Cole, S. T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S. V., Eiglmeier, K., Gas, S., Barry, C. E., III, et al. (1998) Nature 393, 537-544). The deduced amino acid (aa) sequence (443 aa) encoded by Mtb cya contains a single hydrophobic domain of six transmembrane helices (152 aa) in the amino-terminal half of the protein. Flanking this domain are an arginine-rich (17%) amino-terminal cytoplasmic tail (46 aa) and a carboxyl-terminal cytoplasmic domain (245 aa) with extensive homology to the catalytic core of eukaryotic adenylyl cyclases. Site-directed mutagenesis of Arg(43) and Arg(44) to alanine/glycine showed a loss of adenylyl cyclase activity, whereas mutagenesis to lysine restored the activity. Hence it is proposed that the formation of the catalytic site in Mtb adenylyl cyclase requires an interaction between Arg(43) and Arg(44) residues in the distal cytoplasmic tail and the carboxyl-terminal cytoplasmic domain. Mtb adenylyl cyclase activity at the physiological concentration of ATP (1 mm) was 475 nmol of cAMP/min/mg of membrane protein in the presence of Mn(2+) but only 10 nmol of cAMP/min/mg of membrane protein in the presence of Mg(2+). The physiological significance of the activation of Mtb adenylyl cyclase by Mn(2+) is discussed in view of the presence of manganese transporter protein in mycobacteria and macrophages wherein mycobacteria reside.

Breakthrough pain in cancer patients: new therapeutic approaches to an old challenge.

Breakthrough pain is a well recognized but ill-defined phenomenon that occurs commonly in the presence of otherwise stable, persistent pain. It is defined now as a "transient pain episode that occurs, or breaks through from the otherwise stable background pain." Breakthrough pain is usually associated with moderate to severe pain and may form a predictor of poor response to treatment with routine pharmacotherapy. Breakthrough pain is also associated with functional impairment and psychological distress. The assessment and treatment should be multidimensional. Although primary therapies such as chemotherapy, radiation treatment, and surgical options are explored, the mainstay of treatment is pharmacotherapy. Nonpharmacologic methods, such as orthotic devices and joint stabilizations along with behavioral methods, should be explored. Anesthetic and neurosurgical procedures are performed on a limited number of patients based on the prognosis, intractable nature of pain, and favorable risk/benefit ratio. Newer oral transmucosal fentanyl offers a favorable pharmacokinetic and pharmacodynamic profile and ease of administration.

Effect of yoga training on maze learning.

The performance in a maze learning task was assessed in adults of either sex (n = 31) before and after 30 days of yoga training and in an age and gender matched control group of subjects who did not receive training in yoga. Subjects were blind folded and used the dominant hand to trace the path in a wooden pencil maze. At each assessment, subjects were given 5 trials, without a gap between them. Performance was based on the time taken to complete the maze and the number of blind alleys taken. The time and error scores of Trial 1 were significantly less after yoga (two-factor ANOVA, Tukey test). Repeating trials significantly decreased time scores at Trial 5 versus Trial 1, for both groups on Day 1 and for the control group on Day 30. Hence the yoga group showed improved performance in maze tracing at retest 30 days later, which may be related to this group being faster learners and also the effect of yoga itself. Yoga training did not influence maze learning, based on the performance in 5 repeat trials.

Oxygen consumption and respiration following two yoga relaxation techniques.

The present study was conducted to evaluate a statement in ancient yoga texts that suggests that a combination of both "calming" and "stimulating" measures may be especially helpful in reaching a state of mental equilibrium. Two yoga practices, one combining "calming and stimulating" measures (cyclic meditation) and the other, a "calming" technique (shavasan), were compared. The oxygen consumption, breath rate, and breath volume of 40 male volunteers (group mean +/- SD, 27.0 +/- 5.7 years) were assessed before and after sessions of cyclic meditation (CM) and before and after sessions of shavasan (SH). The 2 sessions (CM, SH) were 1 day apart. Cyclic meditation includes the practice of yoga postures interspersed with periods of supine relaxation. During SH the subject lies in a supine position throughout the practice. There was a significant decrease in the amount of oxygen consumed and in breath rate and an increase in breath volume after both types of sessions (2-factor ANOVA, paired t test). However, the magnitude of change on all 3 measures was greater after CM: (1) Oxygen consumption decreased 32.1% after CM compared with 10.1% after SH; (2) breath rate decreased 18.0% after CM and 15.2% after SH; and (3) breath volume increased 28.8% after CM and 15.9% after SH. These results support the idea that a combination of yoga postures interspersed with relaxation reduces arousal more than relaxation alone does.

Pain and loss of function in head and neck cancer survivors.

Head and neck cancers are relatively uncommon malignancies and the characteristics of pain and functional impairments in survivors are not well studied. To characterize the incidence, location, severity, types and causes of pain; associated functional impairments, and pain management methods, the medical charts of 40 consecutive outpatients with biopsy-proven head and neck cancers were reviewed. Pain was severe in 52% (N = 21), and was located near sites of tumor origin. Pain was caused by tumor recurrence in 35% (N = 14), treatment sequelae in 30% (N = 12), multiple etiologies in 25% (N = 10), and unrelated causes in 10% (N = 4). Pains were mixed nociceptive and neuropathic pain in 37.5% (N = 15), nociceptive pain in 32.5% (N = 13), myofascial in 13.0% (N = 6), neuropathic in 7.5% (N = 3); and other mixed types in 7.5% (N = 3). Despite the high prevalence of dysphagia (82%), 60% used orally administered opioid-nonopioid analgesics. Physical disfigurement (87.5%; N = 35), dysphagia (62.5%, N = 25), and jaw dysfunction (40.0%; N = 16) were the most frequent physical impairments. Multiple regression analysis showed that the presence of skull base or mandibular bone involvement had significant influence on the severity of pain (P = 0.03, adjusted R2 0.25) We conclude that pain in head and neck cancer can be chronic, severe, and persistent despite completion of oncologic treatment.