Intravenous heterologous prime-boost vaccination activates innate and adaptive immunity to promote tumor regression.

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 T cells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 T cell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 T cells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans.

Effect of Temperature on Mosquito Olfaction.

Mosquitoes use a wide range of cues to find a host to feed on, eventually leading to the transmission of pathogens. Among them, olfactory cues (e.g., host-emitted odors, including CO2, and skin volatiles) play a central role in mediating host-seeking behaviors. While mosquito olfaction can be impacted by many factors, such as the physiological state of the insect (e.g., age, reproductive state), the impact of environmental temperature on the olfactory system remains unknown. In this study, we quantified the behavioral responses of Aedes aegypti mosquitoes, vectors of dengue, yellow fever, and Zika viruses, among other pathogens, to host and plant-related odors under different environmental temperatures.

Effect of temperature on mosquito olfaction.

Mosquitoes use a wide range of cues to find a host to feed on, eventually leading to the transmission of pathogens. Among them, olfactory cues ( e.g. , host emitted odors, including CO 2 , and skin volatiles) play a central role in mediating host seeking behaviors. While mosquito olfaction can be impacted by many factors, such as the physiological state of the insect ( e.g. , age, reproductive state), the impact of environmental temperature on the olfactory system remains unknown. In this study, we quantified the behavioral responses of Aedes aegypti mosquitoes, vectors of dengue, yellow fever and Zika viruses, to host and plant related odors under different environmental temperatures.

Systemic vaccination induces CD8+ T cells and remodels the tumor microenvironment.

Therapeutic cancer vaccines are designed to increase tumor-specific T cell immunity. However, suppressive mechanisms within the tumor microenvironment (TME) may limit T cell function. Here, we assessed how the route of vaccination alters intratumoral myeloid cells. Using a self-assembling nanoparticle vaccine that links tumor antigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we treated tumor-bearing mice subcutaneously (SNP-SC) or intravenously (SNP-IV). Both routes generated antigen-specific CD8+ T cells that infiltrated tumors. However, only SNP-IV mediated tumor regression, dependent on systemic type I interferon at the time of boost. Single-cell RNA-sequencing revealed that intratumoral monocytes expressing an immunoregulatory gene signature (Chil3, Anxa2, Wfdc17) were reduced after SNP-IV boost. In humans, the Chil3+ monocyte gene signature is enriched in CD16- monocytes and associated with worse outcomes. Our results show that the generation of tumor-specific CD8+ T cells combined with remodeling of the TME is a promising approach for tumor immunotherapy.

Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells.

Personalized cancer vaccines are a promising approach for inducing T cell immunity to tumor neoantigens. Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8+ T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1+PD-1+CD8+ T cells as compared to subcutaneous immunization (SNP-SC). Single-cell RNA sequencing showed that SNP-IV induced stem-like genes (Tcf7, Slamf6, Xcl1) whereas SNP-SC enriched for effector genes (Gzmb, Klrg1, Cx3cr1). Stem-like cells generated by SNP-IV proliferated and differentiated into effector cells upon checkpoint blockade, leading to superior antitumor response as compared to SNP-SC in a therapeutic model. The duration of antigen presentation by dendritic cells controlled the magnitude and quality of CD8+ T cells. These data demonstrate how to optimize antitumor immunity by modulating vaccine parameters for specific generation of effector or stem-like CD8+ T cells.

Visual-Olfactory Integration in the Human Disease Vector Mosquito Aedes aegypti.

Mosquitoes rely on the integration of multiple sensory cues, including olfactory, visual, and thermal stimuli, to detect, identify, and locate their hosts [1-4]. Although we increasingly know more about the role of chemosensory behaviors in mediating mosquito-host interactions [1], the role of visual cues is comparatively less studied [3], and how the combination of olfactory and visual information is integrated in the mosquito brain remains unknown. In the present study, we used a tethered-flight light-emitting diode (LED) arena, which allowed for quantitative control over the stimuli, and a control theoretic model to show that CO2 modulates mosquito steering responses toward vertical bars. To gain insight into the neural basis of this olfactory and visual coupling, we conducted two-photon microscopy experiments in a new GCaMP6s-expressing mosquito line. Imaging revealed that neuropil regions within the lobula exhibited strong responses to objects, such as a bar, but showed little response to a large-field motion. Approximately 20% of the lobula neuropil we imaged were modulated when CO2 preceded the presentation of a moving bar. By contrast, responses in the antennal (olfactory) lobe were not modulated by visual stimuli presented before or after an olfactory stimulus. Together, our results suggest that asymmetric coupling between these sensory systems provides enhanced steering responses to discrete objects.

A sleep diary and questionnaire study of naturally short sleepers.

Whereas most people require more than 6 h of sleep to feel well rested, there appears to be a group of people who can function well on between 3 and 6 h of sleep. The aims of the present study were to compare 12 naturally short (3-6 h) sleepers (9 males 3 females, mean age 39.6 years, SD age 10.1 years) recruited by a media publicity campaign with age, gender and chronotype matched medium length (7-8.5 h) sleepers on various measures. Measurement instruments included diaries and questionnaires to assess sleep duration and timing, as well as questionnaire assessments of sleep pathology, morningness-eveningness, extroversion, neuroticism, pathological daytime sleepiness, subclinical hypomania, optimism, depressive symptoms, exercise, and work habits. Few measures showed reliable differences between naturally short sleepers and controls except the obvious ones related to sleep duration. There was, however, some evidence for subclinical hypomanic symptoms in naturally short sleepers.

Decreased human circadian pacemaker influence after 100 days in space: a case study.

OBJECTIVE: The objectives of this study were (1) to assess the circadian rhythms and sleep of a healthy, 42-year-old male astronaut experiencing microgravity (weightlessness) for nearly 5 months while living aboard Space Station Mir as it orbited Earth and (2) to determine the effects of prolonged space flight on the endogenous circadian pacemaker, as indicated by oral temperature and subjective alertness rhythms, and their ramifications for sleep, alertness, and performance. METHODS: For three 12- to 14-day blocks of time (spread throughout the mission), oral temperatures were taken and subjective alertness was self-rated five times per day. Sleep diaries and performance tests were also completed daily during each block. RESULTS: Examination of the subject's circadian alertness and oral temperature rhythms suggested that the endogenous circadian pacemaker seemed to function quite well up to 90 days in space. Thereafter (on days 110-122), the influence of the endogenous circadian pacemaker on oral temperature and subjective alertness circadian rhythms was considerably weakened, with consequent disruptions in sleep. CONCLUSIONS: Space missions lasting more than 3 months might result in diminished circadian pacemaker influence in astronauts, leading to eventual sleep problems.

Sleep and circadian rhythms in four orbiting astronauts.

This experiment measured the sleep and circadian rhythms of four male astronauts aboard a space shuttle (STS-78) orbiting the Earth for 17 days. The space mission was specially scheduled to minimize disruptions in circadian rhythms and sleep so that the effects of space flight and microgravity per se could be studied. Data were collected in 72-h measurement blocks: one block 7 days before launch, one early within the mission (3 days after launch), one late in the mission (12 days after launch), and one 18 days after landing. Within each measurement block, all sleep was recorded both polysomnographically and by sleep diary. Core body temperature was sampled every 6 mins. Actillumes were worn continuously. All urine samples were collected separately. Performance was assessed by a computerized test battery (3/day) and by end-of-shift questionnaires (1/day); mood and alertness were measured by visual analogue scales (5/day). Circadian rhythms in orbit appeared to be very similar in phase and amplitude to those on the ground, and were appropriately aligned for the required work/rest schedule. There was no change from early flight to late flight. This was also reflected in mood, alertness, and performance scores, which were satisfactory at both in-flight time points. However, in-flight sleep showed a decreased amount of sleep obtained (mean = 6.1 h), and all four astronauts showed a decrease in delta sleep. No further degradation in sleep was seen when early flight was compared to late flight, and no other sleep parameters showed reliable trends.

The effects on human sleep and circadian rhythms of 17 days of continuous bedrest in the absence of daylight.

As part of a larger bedrest study involving various life science experiments, a study was conducted on the effects of 17 days of continuous bedrest and elimination of daylight on circadian rectal temperature rhythms, mood, alertness, and sleep (objective and diary) in eight healthy middle-aged men. Sleep was timed from 2300 to 0700 hours throughout. Three 72-hour measurement blocks were compared: ambulatory prebedrest, early bedrest (days 5-7), and late bedrest (days 15-17). Temperature rhythms showed reduced amplitude and later phases resulting from the bedrest conditions. This was associated with longer nocturnal sleep onset latencies and poorer subjectively rated sleep but with no reliable changes in any of the other sleep parameters. Daily changes in posture and/or exposure to daylight appear to be important determinants of a properly entrained circadian system.

Malignant thyroid lymphoma presenting as acute airway obstruction.

Malignant thyroid lymphoma is an uncommon form of thyroid cancer which most commonly presents in elderly women. Most patients demonstrate a rapidly enlarging mass and may show tracheal deviation on chest roentgenogram. Radioisotopic scanning of the thyroid often demonstrates a "cold" or "cool" process of decreased uptake in the affected area. There is often an underlying lymphocytic thyroiditis process noted. Unfavorable prognosis is related to extracapsular extension, blood vessel wall infiltration, diffuse architectural pattern, and cervical lymph node involvement. We present two unusual cases of thyroid lymphoma presenting with acute airway obstruction and review the literature concerning this subject. One case presented a clinical and radiographic appearance similar to a prevertebral space abscess.

Management of recurrent otitis media.

Recurrent otitis media is defined as three or more episodes of acute otitis media in six months or four or more episodes in one year, with the bouts of acute infection separated by intervals of full resolution. The disorder is common in children and is different from otitis media with effusion, the other frequently encountered chronic ear disease. Daily low-dose antibiotic therapy is recommended as initial prophylaxis against recurrent otitis media. Pressure-equalizing tubes may be used in patients who have more than one episode of breakthrough otitis media while receiving antibiotics. Adenoidectomy should be reserved for use when pressure-equalizing tubes fail or when insertion of a second set of tubes is required.

Subglottic and tracheal malignancies.

Subglottic and tracheal malignancies are the least frequently encountered laryngeal cancers. When these tumors are encountered, they have often reached advanced size prior to producing symptoms. Once symptoms are brought to the attention of the otolaryngologist, rapid and accurate diagnosis is essential to effect the earliest possible treatment and to minimize morbidity and mortality associated with this problem. Illustrative cases are presented including a highly unusual case that presented with cardiac-like chest pain. A review of the literature including the pertinent anatomy, pathophysiology, and methods of diagnosis and treatment is presented. Increased familiarity with this disease process and a high index of suspicion on the part of the otolaryngologist may lead to improved survival patterns in patients with these malignancies.

Indications for tonsillectomy and adenoidectomy.

Tonsillectomy and adenoidectomy are separate procedures that should be performed for distinct reasons. Studies now indicate that severe, recurrent pharyngitis responds well to tonsillectomy. According to separate recommendations from the American Medical Association and the American Academy of Pediatrics, patients are candidates for tonsillectomy if they have four or more episodes of pharyngitis a year. Recurrent otitis media and chronic otitis media are improved by adenoidectomy, although placement of pressure-equalizing tubes remains the preferred initial treatment for these conditions. Adenotonsillectomy improves severe upper airway obstruction (cor pulmonale and obstructive sleep apnea), as well as milder forms of airway obstruction (loud snoring). The effectiveness of these procedures in proposed indications, such as sinusitis and adenoiditis, is less well substantiated.

Toxic shock syndrome associated with pharyngitis and submandibular space abscess.

Toxic shock syndrome continues to be encountered more frequently with the head and neck areas as sources of the toxin. In head and neck surgery practice it is most commonly noted following nasal packing. An unusual case associated with staphylococcal pharyngitis and spontaneous submandibular space abscess is reported and the literature concerning the subject is reviewed. Treatment is eradication of the infective focus, aggressive support of vital functions, and parenteral antistaphylococcal antibiotics.

Schwannoma of the submandibular gland.

Neurilemmomas (schwannomas) are solitary neurogenic tumors that arise from cells of the neural sheath. They are slow growing and represent a proliferation of Schwann cells. Extracranial neurogenic tumors of the head and neck are uncommon, with benign tumors occurring with greater frequency than malignant tumors. These tumors often mimic primary or metastatic disease in the head and neck. Schwannoma of the salivary gland is a particularly rare form of an extracranial neurogenic tumor, with most presenting in the parotid gland originating from a peripheral branch of the facial nerve. An unusual case of neurilemmoma of the submandibular gland is presented, and the literature concerning this subject is reviewed. We believe this tumor originated in an autonomic nerve of the submandibular gland. The mass was discrete and well demonstrated on CT scan. Total excision of the gland resulted in complete resolution of symptoms with no cranial nerve deficits.

Arteriovenous malformation of the maxilla.

The highly vascular nature of the head and neck area provides a particularly enhanced challenge to the head and neck surgeon when a vascular lesion is encountered. Vascular malformations in this area are classified according to the microanatomical architecture and clinical appearance of the lesion. Although bleeding is a common presentation with vascular malformations, other local and systemic problems may be associated with this problem. An unusual case of an arteriovenous malformation of the ethmoid and maxillary sinuses which caused persistent and recurrent epistaxis is presented. A review of the current literature concerning vascular lesions of the head and neck area is included. Adequate treatment of this lesion presently includes angiographically controlled vascular embolization followed by complete surgical excision.

Metastasizing pleomorphic adenoma of the nasal septum.

Pleomorphic adenoma is the most common benign tumor of glandular tissue occurring in the head and neck region. There have been several reports of metastasis of this benign-appearing tumor from the salivary glands to distant sites, suggesting hematogenous spread and implantation. Although occurrence of pleomorphic adenoma on the nasal septum has been described, to our knowledge this is the first reported case of recurrent septal pleomorphic adenoma with histologically benign tissue in an enlarged metastatic ipsilateral submandibular lymph node, suggesting lymphatic spread. The literature concerning the subject is reviewed. Wide septal excision and modified neck dissection is the recommended treatment.

Epiglottic dysfunction after isocyanate inhalation exposure.

Epiglottic dysfunction due to environmental exposure is a well-known entity. The most common causes of epiglottic dysfunction include trauma (thermal, chemical, and blunt), infection, allergy, neoplasm, and neurologic disorders. We report an unusual case of epiglottic dysfunction due to isocyanate inhalation exposure and review the literature concerning this subject. Following inhalation exposure to diphenylmethane diisocyanate, our patient developed persistent repeated airway obstruction during inspiration. Fiberoptic rhinolaryngoscopy showed that the epiglottis obstructed the glottic airway during each inspiratory cycle. The epiglottic dysfunction was also well demonstrated by barium contrast cineradiography. Total epiglottectomy resulted in resolution of the patient's upper airway obstructive symptoms. Histologically, marked inflammatory changes of the epiglottis were noted, including a focal infiltrative pattern, focal fibrosis, edema, and reactive changes.

A comparison of postoperative bleeding incidence between general and local anesthesia tonsillectomies.

Postoperative bleeding after tonsillectomy is a problem that has earned the respect and cautious attention of the most experienced surgeons. The incidence of postoperative hemorrhage after tonsillectomy, as well as many factors affecting this incidence, has been extensively investigated. A possible factor that has not been well studied as a possible influence in postoperative tonsillectomy bleeding is the choice of anesthetic. A study was completed comparing the incidence of postoperative tonsillectomy bleeding between patients operated on using general anesthetic and local anesthetic. One hundred ninety-two patients consecutively undergoing tonsillectomy at Naval Hospital, Oakland, California, were included in the study. Three of 150 patients (3%) having general anesthesia and 13 of 87 patients (15%) having local anesthesia experienced postoperative bleeding. Possible factors influencing this difference in postoperative bleeding incidence are discussed. The possibility is suggested that surgeons (and previous reports) may underestimate the rates of postoperative bleeding as a result of patients being treated by other than the operating physician.