Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/ß-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis.

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/ß-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on ß-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/ß-catenin signaling in CRC cells. Notably, ectopic expression of a dominant-active ß-catenin mutant (∆N90-ß-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/ß-catenin signaling axis.

Randomized clinical trial of accelerated enhanced recovery after minimally invasive colorectal cancer surgery (RecoverMI trial).

BACKGROUND: Minimally invasive surgery (MIS) and enhanced recovery protocols (ERPs) have improved postoperative recovery and shortened length of hospital stay (LOS). Telemedicine technology has potential to improve outcomes and patient experience further. This study was designed to determine whether the combination of MIS, ERP and a structured telemedicine programme (TeleRecovery) could shorten total 30-day LOS by 50 per cent. METHODS: This was a phase II prospective RCT at a large academic medical centre. Eligible patients aged 18-80 years undergoing minimally invasive colorectal resection using an ERP were randomized after surgery. The experimental arm (RecoverMI) included accelerated discharge on postoperative day (POD) 1 with or without evidence of bowel function and a televideoconference on POD 2. The control arm was standard postoperative care. The primary endpoint was total 30-day LOS (postoperative stay plus readmission/emergency department/observation days). Secondary endpoints included patient-reported outcomes measured by EQ-5D-5L™, Brief Pain Inventory (BPI) and a satisfaction questionnaire. RESULTS: Thirty patients were randomized after robotic (21 patients) or laparoscopic (9) colectomy, including 14 patients in the RecoverMI arm. Median 30-day total LOS was 28·3 (i.q.r. 23·7-43·6) h in the RecoverMI arm and 51·5 (43·8-67·0) h in the control arm (P = 0·041). There were no differences in severe adverse events or EQ-5D-5L™ score between the study arms. The BPI revealed low pain scores regardless of treatment arm. Satisfaction was high in both arms. CONCLUSION: In patients having surgery for colorectal neoplasms, the trimodal combination of MIS, ERP and TeleRecovery can reduce 30-day LOS while preserving patients' quality of life and satisfaction. Registration number: NCT02613728 ( https://clinicaltrials.gov).

ANTECEDENTES: La cirugía mínimamente invasiva (minimally invasive surgery, MIS) y los protocolos de recuperación intensificada (enhanced recovery protocols, ERP) han mejorado la recuperación postoperatoria y acortan la duración de la estancia (length of stay, LOS). La tecnología de la telemedicina tiene potencial para mejorar aún más los resultados y la experiencia del paciente. Este estudio se diseñó para determinar si la combinación de MIS, ERP y un programa estructurado de telemedicina (TeleRecovery) podría acortar la LOS total a los 30 días en un 50%. MÉTODOS: Se efectuó un ensayo controlado aleatorizado, prospectivo, de fase II en un gran centro médico académico. Los pacientes elegibles de 18-80 años de edad que se sometieron a resección colorrectal MIS mediante ERP se asignaron al azar después de la resección quirúrgica. El brazo experimental (RecoverMI) incluyó el alta acelerada en el día 1 del postoperatorio (postoperative day, POD) con o sin evidencia de recuperación del tránsito intestinal y una televideoconferencia en el día 2 POD. Los pacientes en el grupo control recibieron los cuidados postoperatorios habituales. El criterio de valoración principal fue la LOS total (estancia postoperatoria más reingreso/estancia en urgencias/días de observación) a los 30 días. Los criterios de valoración secundarios incluyeron los resultados referidos por los pacientes medidos por los cuestionarios EQ-5D-5L, el Cuestionario Breve del Dolor (Brief Pain Inventory, BPI) y un cuestionario de satisfacción. RESULTADOS: Treinta pacientes fueron aleatorizados después de una colectomía robótica (21) o laparoscópica (9), incluidos 14 pacientes en el grupo de RecoverMI. La mediana de la LOS total a los 30 días fue de 28,3 horas (rango intercuartílico, RIQ 23,7-43,6) en el grupo de RecoverMI y de 51,5 horas (RIQ 43,8-67,0) en el grupo control (P = 0,04). No hubo diferencias entre los grupos de estudio en los eventos adversos graves o en las puntuaciones del EQ-5D-5L. El BPI mostró puntuaciones bajas de dolor independientemente del grupo de tratamiento. La satisfacción fue alta en ambos grupos. CONCLUSIÓN: Entre los pacientes que se someten a cirugía por cáncer colorrectal, la combinación trimodal de MIS, ERP y TeleRecovery puede reducir la LOS a los 30 días, preservando la calidad de vida y la satisfacción del paciente.

X-ray crystal structures, density functional theory and docking on deacetylase enzyme for antiproliferative activity of hispolon derivatives on HCT116 colon cancer.

The antiproliferative action of hispolon derivatives is stronger than that of related curcumin against several tumor cell lines. Hispolon size, smaller than curcumin, fits better than curcumin into the active site of HDAC6, an enzyme involved in deacetylation of lysine residues. HDACs are considered potential targets for tumor drug discovery and hydroxamates are known inhibitors of HDACs. One of them, SAHA (Vorinostat) is used in clinical studies. Investigations into possible mechanisms for hispolon derivatives active against the HCT116 colon tumor cell line are done after examining the structural results obtained from hispolon X-ray crystal structures as well as performing associated computational docking and Density Functional Theory techniques on HDAC6. These studies show preference for the HDAC6 active site by chelating the Zn center, in contrast with other ineffective hispolon derivatives, that establish only a single bond to the metal center. Structure activity relationships make clear that hydrogenation of the hispolon bridge also leads to single bond (non chelate) hispolon-Zn binding, and consistently nullifies the antiproliferative action against HCT116 tumor.

Effect of beta-blockers on cancer recurrence and survival: a meta-analysis of epidemiological and perioperative studies.

BACKGROUND: The biological perturbation associated with psychological and surgical stress is implicated in cancer recurrence. Preclinical evidence suggests that beta-blockers can be protective against cancer progression. We undertook a meta-analysis of epidemiological and perioperative clinical studies to investigate the association between beta-blocker use and cancer recurrence (CR), disease-free survival (DFS), and overall survival (OS). METHODS: Databases were searched until September 2017, reported hazard ratios (HRs) pooled, and 95% confidence intervals (CIs) calculated. Comparative studies examining the effect of beta-blockers (selective and non-selective) on cancer outcomes were included. The Newcastle Ottawa Scale was used to assess methodological quality and bias. RESULTS: Of the 27 included studies, nine evaluated the incidental use of non-selective beta-blockers, and ten were perioperative studies. Beta-blocker use had no effect on CR. Within subgroups of cancer, melanoma was associated with improved DFS (HR 0.03, 95% CI 0.01-0.17) and OS (HR 0.04, 95% CI 0.00-0.38), while endometrial cancer had an associated reduction in DFS (HR 1.40, 95% CI 1.10-1.80) and OS (HR 1.50, 95% CI 1.12-2.00). There was also reduced OS seen with head and neck and prostate cancer. Non-selective beta-blocker use was associated with improved DFS and OS in ovarian cancer, improved DFS in melanoma, but reduced OS in lung cancer. Perioperative studies showed similar variable effects across cancer types, albeit from a limited data pool. CONCLUSION: Beta-blocker use had no evident effect on CR. The beneficial effect of beta-blockers on DFS and OS in the epidemiological or perioperative setting remains variable, tumour-specific, and of low-level evidence at present.

Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers.

BACKGROUND: Perioperative strategies can significantly influence long-term cancer outcomes. Dexmedetomidine, an α2-adrenoceptor agonist, is increasingly used perioperatively for its sedative, analgesic, anxiolytic, and sympatholytic effects. Such actions might attenuate the perioperative promotion of metastases, but other findings suggest opposite effects on primary tumour progression. We tested the effects of dexmedetomidine in clinically relevant models of dexmedetomidine use on cancer metastatic progression. METHODS: Dexmedetomidine was given to induce sub-hypnotic to sedative effects for 6-12 h, and its effects on metastasis formation, using various cancer types, were studied in naïve animals and in the context of stress and surgery. RESULTS: Dexmedetomidine increased tumour-cell retention and growth of metastases of a mammary adenocarcinoma (MADB 106) in F344 rats, Lewis lung carcinoma (3LL) in C57BL/6 mice, and colon adenocarcinoma (CT26) in BALB/c mice. The metastatic burden increased in both sexes and in all organs tested, including lung, liver, and kidney, as well as in brain employing a novel external carotid-artery inoculation approach. These effects were mediated through α2-adrenergic, but not α1-adrenergic, receptors. Low sub-hypnotic doses of dexmedetomidine were moderately beneficial in attenuating the deleterious effects of one stress paradigm, but not of the surgery or other stressors. CONCLUSIONS: The findings call for mechanistic translational studies to understand these deleterious effects of dexmedetomidine, and warrant prospective clinical trials to assess the impact of perioperative dexmedetomidine use on outcomes in cancer patients.

Systematic review and consensus definitions for standardised endpoints in perioperative medicine: postoperative cancer outcomes.

BACKGROUND: The Standardising Endpoints for Perioperative Medicine group was established to derive an appropriate set of endpoints for use in clinical trials related to anaesthesia and perioperative medicine. Anaesthetic or analgesic technique during cancer surgery with curative intent may influence the risk of recurrence or metastasis. However, given the current equipoise in the existing literature, prospective, randomised, controlled trials are necessary to test this hypothesis. As such, a cancer subgroup was formed to derive endpoints related to research in onco-anaesthesia based on a current evidence base, international consensus and expert guidance. METHODS: We undertook a systematic review to identify measures of oncological outcome used in the oncological, surgical, and wider literature. A multiround Delphi consensus process that included up to 89 clinician-researchers was then used to refine a recommended list of endpoints. RESULTS: We identified 90 studies in a literature search, which were the basis for a preliminary list of nine outcome measures and their definitions. A further two were added during the Delphi process. Response rates for Delphi rounds one, two, and three were 88% (n=9), 82% (n=73), and 100% (n=10), respectively. A final list of 10 defined endpoints was refined and developed, of which six secured approval by ≥70% of the group: cancer health related quality of life, days alive and out of hospital at 90 days, time to tumour progression, disease-free survival, cancer-specific survival, and overall survival (and 5-yr overall survival). CONCLUSION: Standardised endpoints in clinical outcomes studies will support benchmarking and pooling (meta-analysis) of trials. It is therefore recommended that one or more of these consensus-derived endpoints should be considered for inclusion in clinical trials evaluating a causal effect of anaesthesia-analgesia technique on oncological outcomes.

Assessing the impact of perioperative blood transfusions on the survival of adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for appendiceal carcinomatosis.

BACKGROUND AND OBJECTIVES: Perioperative red blood cell transfusions (PBT) may be associated with worse survival. In this study of adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), we investigated whether there was an association between PBT and survival. MATERIALS AND METHODS: A retrospective study of adults who had undergone CRS-HIPEC for appendiceal carcinomatosis was conducted. Univariate and multivariate analyses were used to identify factors associated with survival. RESULTS: Of the 270 patients analysed, 170 (63%) received PBT. A PBT was not significantly associated with recurrence-free survival (RFS) (HR = 1·03; 95% CI: 0·7-1·51; P = 0·879) or overall survival (OS) (HR = 0·65; 95% CI: 0·38-1·11; P = 0·116). Higher number of PBT units (≥5) was not associated with worse RFS (P = 0·077) or OS (P = 0·079). Independent predictors of poor survival included as follows: estimated blood loss and high tumour grade for RFS (both P < 0·001), and male gender (P = 0·029) and high tumour grade (P < 0·001) for OS. Higher preoperative haemoglobin was independently associated with better RFS (P = 0·011) and OS (P = 0·006). CONCLUSIONS: In this retrospective study of adults who had undergone CRS-HIPEC for appendiceal carcinomatosis, PBT was not significantly associated with survival.

Synthesis, screening and docking analysis of hispolon analogs as potential antitubercular agents.

A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6µg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25µg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6µg/mL) followed by H13 (6.25µg/mL) and H17 (12.5µg/mL), H19 (3.125µg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and ß-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH.

Non-steroidal anti-inflammatory drugs in the oncological surgical population: beneficial or harmful? A systematic review of the literature.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesic drugs. Recent studies have indicated a potential beneficial effect on long-term survival outcomes after cancer surgery but a negative impact on anastomotic leaks. The objective of this study was to objectively assess the implications of the perioperative NSAIDs use on anastomotic leaks and cancer recurrence. METHODS: We searched PubMed, MEDLINE, Embase and Cochrane Library for publications up to mid-January 2017. Randomized controlled trials (RCTs) and observational studies in adults undergoing cancer surgery were included for quality assessment. We excluded animal studies, in vitro experiments and case reports. The selected sudies were graded using the Jadad score or Newcastle-Ottawa scale for RCTs and observational retrospective studies, respectively. RESULTS: The systematic review identified 25 trials that explored the impact of NSAIDs on anastomotic leaks and 16 trials that assessed the association between perioperative NSAIDs and cancer recurrence. Meta-analyses were not performed because of high heterogeneity and low quality of the included studies. CONCLUSIONS: The literature is not conclusive on whether the use of NSAIDs is associated with anastomotic leaks after gastrointestinal cancer surgery. Also, the current evidence is equivocal regarding the effects of short-term NSAIDs on cancer recurrence after major cancer surgery. Three RCTs are being conducted to assess the impact of NSAIDs on cancer recurrence. There are no registered RCTs that are testing the hypothesis of whether the perioperative use of NSAIDs increases the rate of anastomotic leaks.

Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs.

Phytochemicals play an important role in cancer therapy. Hispolon and 26 of its analogs (9 known and 17 new) were synthesized and evaluated for their antiproliferative activities in a panel of six independent human cancer cell lines using the in vitro cell-based MTT assay. Among the hispolon analogs tested, compound VA-2, the most potent overall, produced its most significant effect in the colon cancer cell lines HCT-116 (IC50 1.4 ± 1.3 µM) and S1 (IC50 1.8 ± 0.9 µM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC50 15.8±3.7 µM; p<0.01 for each comparison). Based on our results, VA-2 was about 9- to 11-times more potent in colon cancer cells and 2- to 3-times more potent in prostate cancer cells compared to HEK293/pcDNA3.1 cells. Morphological analysis of VA-2 showed significant reduction of cell number, while the cells' sizes were also markedly increased and were obvious at 68 h of treatment with 1 µM in HCT-116 (colon) and PC-3 (prostate) cancer cells. A known analog, compound VA-4, prepared by simple modifications on the aromatic functional groups of hispolon, inhibited prostate and colon cancer cell lines with IC50 values <10 µM. In addition, hispolon isoxazole and pyrazole analogs, VA-7 and VA-15 (known), respectively, have shown significant activity with the mean ICv values in the range 3.3-10.7 µM in all the cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and ß-diketone functional groups are modified. But the activity of analogs VA-16 to VA-27 was completely lost when the side chain double-bond was hydrogenated indicating the crucial role of this functionality for anticancer activity. Furthermore, many of the compounds synthesized were not substrates for the ABCB1-transporter, the most common cause of multidrug resistance in anti-cancer drugs, suggesting they may be more effective anticancer agents.

Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions.

Debate on appropriate triggers for transfusion of allogeneic blood products and their effects on short- and long-term survival in surgical and critically ill patients continue with no definitive evidence or decisive resolution. Although transfusion-related immune modulation (TRIM) is well established, its influence on immune competence in the recipient and its effects on cancer recurrence after a curative resection remains controversial. An association between perioperative transfusion of allogeneic blood products and risk for recurrence has been shown in colorectal cancer in randomized trials; whether the same is true for other types of cancer remains to be determined. This article focuses on the laboratory, animal, and clinical evidence to date on the mechanistic understanding of inflammatory and immune-modulatory effects of blood products and their significance for recurrence in the cancer surgical patient.

Postoperative complications in obstructive sleep apnea.

STUDY OBJECTIVES: This study was conducted to determine whether postoperative complications are increased in patients with obstructive sleep apnea (OSA) and to study the impact of the severity of OSA and preoperative use of continuous positive airway pressure (CPAP) on the postoperative outcome. DESIGN AND SETTING: This study is retrospective in nature and was undertaken at the VA Medical Center. PARTICIPANTS AND METHODS: Three hundred seventy patients who had undergone both a major surgical procedure and a sleep study from 2000 to 2010 were identified. Patients were divided into four groups: OSA negative (apnea-hypopnea index (AHI) < 5/h), OSA positive; mild: AHI 5 to <15/h; moderate: AHI 15 to <30/h; and severe: AHI ≥ 30/h. No intervention was made during the course of the study. Postoperative complications namely respiratory, cardiac, neurological, and unplanned intensive care unit transfers were collected. RESULTS: There were 284 (76.8 %) patients having OSA and 86 (23.2 %) without OSA. The overall incidence of total complications was significantly higher in the OSA patients compared with the control patients (48.9 vs. 31.4 %; odds ratio 2.09, 95 % CI 1.25-3.49). There was no significant difference in total complications between those using and not using CPAP prior to hospitalization. Patients with sleep apnea had a higher incidence of respiratory complications compared to patients without sleep apnea (40.4 vs. 23.2 %; odds ratio 2.24, 95 % CI 1.29-3.90). There was no significant difference in major cardiac complications in the OSA patients compared with the control patients (13.0 vs. 9.3 %; odds ratio 1.46, 95 % CI 0.65-3.26). CONCLUSION: OSA is associated with a significantly increased rate of postoperative complications.

Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether.

Colorectal cancer (CRC) is the third most prevalent human cancer globally. 5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving CRC malignant transformation and a poor prognostic marker for CRC, underscoring STAT3 as a promising CRC drug target. Dehydroxyhispolon methyl ether (DHME) is an analog of Hispolon, an anticancer polyphenol abundant in the medicinal mushroom Phellinus linteus. Previously, we have established DHME's cytotoxic effect on human CRC cell lines by eliciting apoptosis through the blockade of WNT/ß-catenin signaling, a preeminent CRC oncogenic pathway. Herein, we unraveled that compared with 5-FU, DHME is a more potent killer of CRC cells while being much less toxic to normal colon epithelial cells. DHME suppressed both constitutive and interleukin 6 (IL-6)-induced STAT3 activation represented by tyrosine 705 phosphorylation of STAT3 (p-STAT3 (Y705)); notably, DHME-induced CRC apoptosis and clonogenicity limitation were abrogated by ectopic expression of STAT3-C, a dominant-active STAT3 mutant. Additionally, we proved that BCL-2 downregulation caused by DHME-mediated STAT3 blockage is responsible for DHME-induced CRC cell apoptosis. Lastly, DHME inhibited SRC activation, and v-src overexpression restored p-STAT3 (Y705) levels along with lowering the levels of apoptosis in DHME-treated CRC cells. We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/ß-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.

Methoxyhispolon Methyl Ether, a Hispolon Analog, Thwarts the SRC/STAT3/BCL-2 Axis to Provoke Human Triple-Negative Breast Cancer Cell Apoptosis In Vitro.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with few treatment options. A promising TNBC treatment approach is targeting the oncogenic signaling pathways pivotal to TNBC initiation and progression. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving TNBC malignant transformation, highlighting STAT3 as a promising TNBC therapeutic target. Methoxyhispolon Methyl Ether (MHME) is an analog of Hispolon, an anti-cancer polyphenol found in the medicinal mushroom Phellinus linteus. Still, MHME's anti-cancer effects and mechanisms remain unknown. Herein, we present the first report about MHME's anti-TNBC effect and its action mechanism. We first revealed that MHME is proapoptotic and cytotoxic against human TNBC cell lines HS578T, MDA-MB-231, and MDA-MB-463 and displayed a more potent cytotoxicity than Hispolon's. Mechanistically, MHME suppressed both constitutive and interleukin 6 (IL-6)-induced activation of STAT3 represented by the extent of tyrosine 705-phosphorylated STAT3 (p-STAT3). Notably, MHME-evoked apoptosis and clonogenicity impairment were abrogated in TNBC cells overexpressing a dominant-active mutant of STAT3 (STAT3-C); supporting the blockade of STAT3 activation is an integral mechanism of MHME's cytotoxic action on TNBC cells. Moreover, MHME downregulated BCL-2 in a STAT3-dependent manner, and TNBC cells overexpressing BCL-2 were refractory to MHME-induced apoptosis, indicating that BCL-2 downregulation is responsible for MHME's proapoptotic effect on TNBC cells. Finally, MHME suppressed SRC activation, while v-src overexpression rescued p-STAT3 levels and downregulated apoptosis in MHME-treated TNBC cells. Collectively, we conclude that MHME provokes TNBC cell apoptosis through the blockade of the SRC/STAT3/BCL-2 pro-survival axis. Our findings suggest the potential of applying MHME as a TNBC chemotherapy agent.

Do patients at risk of sleep apnea have an increased risk of cardio-respiratory complications during endoscopy procedures?

BACKGROUND: Patients with sleep apnea (OSA) have an increased risk of perioperative complications. AIM: The purpose of this study is to assess whether OSA increases the risk of cardio-respiratory complications in patients undergoing endoscopic procedures with conscious sedation. METHODS: A prospective study over a 7-month period was performed. All patients undergoing upper, lower, or combined endoscopy were asked to fill in the Berlin questionnaire. The questionnaire was scored, and patients were classified as high or low risk for sleep apnea based on the suggested scoring criteria. Patients who had previously undergone a sleep study were excluded. Demographics and co-morbidities were identified from the electronic medical record. Procedure type, amount of sedation, and minor and major complications were identified from the endoscopy flow sheet. The minor complications were defined as hypertension, hypotension, bradycardia, tachycardia, hypoxemia, and bradypnea (respiratory rate <8 breaths/min). Major complications included chest pain, arrhythmia, altered mental status, respiratory distress, and a minor complication that required a significant intervention, such as use of a reversal agent, atropine, up-titration of oxygen for hypoxemia, or prolonged observation. RESULTS: Procedures were performed in 904 patients: colonoscopies, 68.0%; upper endoscopies, 22.8%; and combined procedures, 9.2%. Five hundred fifty-three patients were identified as low risk (61.2%), and 351 were identified as high risk (38.8%). The mean age was 59.5 ± 10.5 years, mean body mass index was 28.9 ± 6.6, mean neck circumference was 16.2 ± 6.3 in., and 91.4% were males. The median Charlson co-morbidity index was 1 (25-75% percentage range 0-2). All patients received midazolam and fentanyl during endoscopy. The median and 25-75% range for midazolam and fentanyl dosages were 5 mg, 4-6 mg and 100 µg, 75-125 µg, respectively. Minor complications were observed in 10.56% of low-risk patients and 10.63% of high-risk patients (p = not significant (NS); odds ratio, 1.01; 95% confidence interval 0.65-1.56). Major complications were observed in 3.25% of low-risk patients and 1.9% of high-risk patients (p = ns; odds ratio, 0.6; 95% confidence interval 0.26-1.46). CONCLUSION: For patients undergoing endoscopy procedures under conscious sedation, the presence of OSA does not clearly increase the risk of cardiopulmonary complications.

Are the adverse effects of body position in patients with obstructive sleep apnea dependent on sleep stage?

PURPOSE: The purpose of the study was to determine if the adverse effect of body position on obstructive sleep apnea (OSA) is worsened during rapid eye movement (REM) sleep and if patients with OSA decrease the time spent supine during REM sleep. METHODS: Overnight polysomnography from 80 sequential patients referred to Buffalo VA Sleep Lab for suspected OSA were analyzed with 20 patients in each of the following groups: normal with apnea-hypopnea indices (AHI) <5/h, mild (AHI, 5-< 15/h), moderate (AHI, 15-<30/h), and severe (AHI, >30/h). We used extended Cox models with the Anderson-Gill modification for multiple events with two time varying covariates: sleep stage and body position. Generalized estimating equations with logit link were used to take into account correlated data within each patient for the relation between sleep stage and body position. RESULTS: The hazard ratios for events in REM vs non-REM sleep was significant for the normal, mild, and moderate groups only: 1.71 (95% CI 1.4-2.08), 1.45 (95% CI 1.22-1.73), 1.28 (95% CI 1.1-1.5), respectively. The hazard ratio for events in the supine vs non-supine position was significant for the mild and moderate groups only: 1.25 (95% CI 1.02-1.52) and 1.24 (95% CI 1.04-1.47), respectively. The addition of an interaction effect between sleep stage and body position was not statistically significant for any group. The odds ratios of sleeping in supine position for REM vs non-REM sleep were 0.47 (95% CI 0.27-0.82) for moderate OSA group and 0.54 (95% CI 0.3-0.95) for severe OSA. CONCLUSION: In summary, we found significant effects of both sleep stage and body position in mild and moderate but not severe OSA. Patients with moderate and severe OSA were less likely to spend time in the supine position during REM compared with non-rapid eye movement sleep.

Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-kappa-B, cyclooxygenase and tumor cell proliferation.

Investigation of the methanol extract of Aswagandha (Withania somnifera) roots for bioactive constituents yielded a novel withanolide sulfoxide compound (1) along with a known withanolide dimer ashwagandhanolide (2) with an S-linkage. The structure of compound 1 was established by extensive NMR and MS experiments. Compound 1 was highly selective in inhibiting cyclooxygenase-2 (COX-2) enzyme by 60% at 100 microm with no activity against COX-1 enzyme. The IC(50) values of compound 1 against human gastric (AGS), breast (MCF-7), central nervous system (SF-268) and colon (HCT-116) cancer cell lines were in the range 0.74-3.63 microm. Both S-containing dimeric withanolides, 1 and 2, completely suppressed TNF-induced NF-kappaB activation when tested at 100 microm. The isolation of a withanolide sulfoxide from W. somnifera roots and its ability to inhibit COX-2 enzyme and to suppress human tumor cell proliferation are reported here for the first time. In addition, this is the first report on the abrogation of TNF-induced NF-kappaB activation for compounds 1 and 2.

Synthesis, Screening and Docking Analysis of Hispolon Pyrazoles and Isoxazoles as Potential Antitubercular Agents.

BACKGROUND: Hispolons are natural products known to possess cytoprotective, antioxidant and anti-cancer activities. We have found recently anti TB activity in these compounds. Efforts were made to optimize the structure with bioisosteric replacement of 1,3-diketo functional group with the corresponding pyrazole and isoxazole moieties. OBJECTIVE: The goal of this paper is designing new hispolon isoxazole and pyrazole and the evaluation of their biological activities. METHODS: The designed compounds were prepared using classical organic synthesis methods. The anti- TB activity was evaluated using the MABA method. RESULTS: A total of 44 compounds were synthesized (1a- 1v and 2a-2v) and screened for anti TB activity and antibacterial activity. The compounds 1b and 1n showed the highest potency with MIC 1.6µg/mL against M. tuberculosis H37Rv. CONCLUSION: Bioisosteric replacement of 1,3-diketo functional group in hispolons with pyrazole or isoxazole rings have resulted in potent anti TB molecules. Docking simulations of these compounds on mtFabH enzyme resulted in a clear understanding of bioactivity profiles of these compounds. Docking scores are in good agreement with the anti TB activity obtained for these compounds. Computational studies and in vitro screening results indicate mtFabH as the probable target of these compounds.