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Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.

Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.

CD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center (GC) response is an important question as we investigate vaccine induced immunity against COVID-19. Here, we report that SARS-CoV-2 infection in rhesus macaques, either infused with convalescent plasma, normal plasma, or receiving no infusion, resulted in transient accumulation of pro-inflammatory monocytes and proliferating Tfh cells with a Th1 profile in peripheral blood. CD4 helper cell responses skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. SARS-CoV-2 Infection induced GC Tfh cells specific for the SARS-CoV-2 spike and nucleocapsid proteins, and a corresponding early appearance of antiviral serum IgG antibodies. Collectively, the data show induction of GC responses in a rhesus model of mild COVID-19.

There is an urgent need for effective therapeutic interventions against SARS-CoV-2, including new variants that continue to arise. Neutralizing monoclonal antibodies have shown promise in clinical studies. We investigated the therapeutic efficacy of a combination of two potent monoclonal antibodies, C135-LS and C144-LS that carry half-life extension mutations, in the rhesus macaque model of COVID-19. Twelve young adult macaques (three groups of four animals) were inoculated intranasally and intra-tracheally with a high dose of SARS-CoV-2 and 24 hours later, treated intravenously with a high (40 mg/kg) or low (12 mg/kg) dose of the C135-LS and C144-LS antibody combination, or a control monoclonal antibody. Animals were monitored for 7 days. Compared to the control animals, animals treated with either dose of the anti-SARS-CoV-2 antibodies showed similarly improved clinical scores, lower levels of virus replication in upper and lower respiratory tract, and significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. In conclusion, this study provides proof-of-concept in support of further clinical development of these monoclonal antibodies against COVID-19 during early infection.

CD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center (GC) response is an important question as we investigate vaccine induced immunity against COVID-19. Here, we report that SARS-CoV-2 infection in rhesus macaques, either infused with convalescent plasma, normal plasma, or receiving no infusion, resulted in transient accumulation of pro-inflammatory monocytes and proliferating Tfh cells with a Th1 profile in peripheral blood. CD4 helper cell responses skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. SARS-CoV-2 Infection induced GC Tfh cells specific for the SARS-CoV-2 spike and nucleocapsid proteins, and a corresponding early appearance of antiviral serum IgG antibodies. Collectively, the data show induction of GC responses in a rhesus model of mild COVID-19.

The human retina contains three classes of cone photoreceptors each sensitive to different portions of the visual spectrum: long (L), medium (M) and short (S) wavelengths. Color information is computed by downstream neurons that compare relative activity across the three cone types. How cone signals are combined at a cellular scale has been more difficult to resolve. This is especially true near the fovea, where spectrally-opponent neurons in the parvocellular pathway draw excitatory input from a single cone and thus even the smallest stimulus projected through natural optics will engage multiple color-signaling neurons. We used an adaptive optics microstimulator to target individual and pairs of cones with light. Consistent with prior work, we found that color percepts elicited from individual cones were predicted by their spectral sensitivity, although there was considerable variability even between cones within the same spectral class. The appearance of spots targeted at two cones were predicted by an average of their individual activations. However, two cones of the same subclass elicited percepts that were systematically more saturated than predicted by an average. Together, these observations suggest both spectral opponency and prior experience influence the appearance of small spots.

The human retina contains three classes of cone photoreceptors each sensitive to different portions of the visual spectrum: long (L), medium (M) and short (S) wavelengths. Color information is computed by downstream neurons that compare relative activity across the three cone types. How cone signals are combined at a cellular scale has been more difficult to resolve. This is especially true near the fovea, where spectrally-opponent neurons in the parvocellular pathway draw excitatory input from a single cone and thus even the smallest stimulus projected through natural optics will engage multiple color-signaling neurons. We used an adaptive optics microstimulator to target individual and pairs of cones with light. Consistent with prior work, we found that color percepts elicited from individual cones were predicted by their spectral sensitivity, although there was considerable variability even between cones within the same spectral class. The appearance of spots targeted at two cones were predicted by an average of their individual activations. However, two cones of the same subclass elicited percepts that were systematically more saturated than predicted by an average. Together, these observations suggest both spectral opponency and prior experience influence the appearance of small spots.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.

Color vision requires the activity of cone photoreceptors to be compared in post-receptoral circuitry. Decades of psychophysical measurements have quantified the nature of these comparative interactions on a coarse scale. How such findings generalize to a cellular scale remains unclear. To answer that question, we quantified the influence of surrounding light on the appearance of spots targeted to individual cones. The eyes aberrations were corrected with adaptive optics and retinal position was precisely tracked in real-time to compensate for natural movement. Subjects reported the color appearance of each spot. A majority of L-and M-cones consistently gave rise to the sensation of white, while a smaller group repeatedly elicited hue sensations. When blue sensations were reported they were more likely mediated by M- than L-cones. Blue sensations were elicited from M-cones against a short-wavelength light that preferentially elevated the quantal catch in surrounding S-cones, while stimulation of the same cones against a white background elicited green sensations. In one of two subjects, proximity to S-cones increased the probability of blue reports when M-cones were probed. We propose that M-cone increments excited both green and blue opponent pathways, but the relative activity of neighboring cones favored one pathway over the other.

Color vision requires the activity of cone photoreceptors to be compared in post-receptoral circuitry. Decades of psychophysical measurements have quantified the nature of these comparative interactions on a coarse scale. How such findings generalize to a cellular scale remains unclear. To answer that question, we quantified the influence of surrounding light on the appearance of spots targeted to individual cones. The eye's aberrations were corrected with adaptive optics and retinal position was precisely tracked in real-time to compensate for natural movement. Subjects reported the color appearance of each spot. A majority of L-and M-cones consistently gave rise to the sensation of white, while a smaller group repeatedly elicited hue sensations. When blue sensations were reported they were more likely mediated by M- than L-cones. Blue sensations were elicited from M-cones against a short-wavelength light that preferentially elevated the quantal catch in surrounding S-cones, while stimulation of the same cones against a white background elicited green sensations. In one of two subjects, proximity to S-cones increased the probability of blue reports when M-cones were probed. We propose that M-cone increments excited both green and blue opponent pathways, but the relative activity of neighboring cones favored one pathway over the other.

Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that chronic cancer pain as well as high-dose opioid use lead to mu-opioid receptor downregulation. In this study we explore downregulation of the mu-opioid receptor gene (OPRM1), as a mechanism for opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high-dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on 2 main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons.PerspectiveWe demonstrate that epigenetic regulation of OPRM1 contributes to opioid tolerance in cancer patients, and that targeted gene therapy could treat cancer-induced nociception and opioid tolerance in a mouse cancer model.

ContextFatigue is the most common symptom in oncology patients during chemotherapy. Little is known about the predictors of interindividual variability in initial levels and trajectories of morning fatigue severity in these patients.ObjectivesAn evaluation was done to determine which demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of morning fatigue and to compare findings with our companion paper on evening fatigue.MethodsA sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (n = 586) completed demographic and symptom questionnaires a total of six times over two cycles of chemotherapy. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling was used to answer the study objectives.ResultsA large amount of interindividual variability was found in the morning fatigue trajectories. A piecewise model fit the data best. Patients with higher body mass index, who did not exercise regularly, with a lower functional status, and who had higher levels of state anxiety, sleep disturbance, and depressive symptoms reported higher levels of morning fatigue at enrollment. Variations in the trajectories of morning fatigue were predicted by the patients' ethnicity and younger age.ConclusionThe modifiable risk factors that were associated with only morning fatigue were body mass index, exercise, and state anxiety. Modifiable risk factors that were associated with both morning and evening fatigue included functional status, depressive symptoms, and sleep disturbance. Using this information, clinicians can identify patients at higher risk for more severe morning fatigue and evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors.

ContextFatigue is a distressing persistent sense of physical tiredness that is not proportional to a person's recent activity. Fatigue impacts patients' treatment decisions and can limit their self-care activities. Although significant interindividual variability in fatigue severity has been noted, little is known about predictors of interindividual variability in initial levels and trajectories of evening fatigue severity in oncology patients receiving chemotherapy.ObjectivesTo determine whether demographic, clinical, and symptom characteristics were associated with initial levels and the trajectories of evening fatigue.MethodsA sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N = 586) completed demographic and symptom questionnaires a total of six times over two cycles of chemotherapy. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling was used to answer the study objectives.ResultsA large amount of interindividual variability was found in the evening fatigue trajectories. A piecewise model fit the data best. Patients who were white, diagnosed with breast, gynecological, or lung cancer, and who had more years of education, childcare responsibilities, lower functional status, and higher levels of sleep disturbance and depression reported higher levels of evening fatigue at enrollment.ConclusionThis study identified both nonmodifiable (e.g., ethnicity) and modifiable (e.g., childcare responsibilities, depressive symptoms, sleep disturbance) risk factors for more severe evening fatigue. Using this information, clinicians can identify patients at higher risk for more severe evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors.

BackgroundA large amount of interindividual variability exists in the occurrence of symptoms in patients receiving chemotherapy (CTX). The purposes of the current study, which was performed in a sample of 582 oncology outpatients who were receiving CTX, were to identify subgroups of patients based on their distinct experiences with 25 commonly occurring symptoms and to identify demographic and clinical characteristics associated with subgroup membership. In addition, differences in quality of life outcomes were evaluated.MethodsOncology outpatients with breast, gastrointestinal, gynecological, or lung cancer completed the Memorial Symptom Assessment Scale before their next cycle of CTX. Latent class analysis was used to identify subgroups of patients with distinct symptom experiences.ResultsThree distinct subgroups of patients were identified (ie, 36.1% in Low class; 50.0% in Moderate class, and 13.9% in All High class). Patients in the All High class were significantly younger and more likely to be female and nonwhite, and had lower levels of social support, lower socioeconomic status, poorer functional status, and a higher level of comorbidity.ConclusionsFindings from the current study support the clinical observation that some oncology patients experience a differentially higher symptom burden during CTX. These high-risk patients experience significant decrements in quality of life.

Because multiple symptoms associated with "sickness behavior" have a negative impact on functional status and quality of life, increased information on the mechanisms that underlie inter-individual variability in this symptom experience is needed. The purposes of this study were to determine: if distinct classes of individuals could be identified based on their experience with pain, fatigue, sleep disturbance, and depression; if these classes differed on demographic and clinical characteristics; and if variations in pro- and anti- inflammatory cytokine genes were associated with latent class membership. Self-report measures of pain, fatigue, sleep disturbance, and depression were completed by 168 oncology outpatients and 85 family caregivers (FCs). Using latent class profile analysis (LCPA), three relatively distinct classes were identified: those who reported low depression and low pain (83%), those who reported high depression and low pain (4.7%), and those who reported high levels of all four symptoms (12.3%). The minor allele of IL4 rs2243248 was associated with membership in the "All high" class along with younger age, being White, being a patient (versus a FC), having a lower functional status score, and having a higher number of comorbid conditions. Findings suggest that LPCA can be used to differentiate distinct phenotypes based on a symptom cluster associated with sickness behavior. Identification of distinct phenotypes provides new evidence for the role of IL4 in the modulation of a sickness behavior symptom cluster in oncology patients and their FCs.

Because multiple symptoms associated with "sickness behavior" have a negative impact on functional status and quality of life, increased information on the mechanisms that underlie inter-individual variability in this symptom experience is needed. The purposes of this study were to determine: if distinct classes of individuals could be identified based on their experience with pain, fatigue, sleep disturbance, and depression; if these classes differed on demographic and clinical characteristics; and if variations in pro- and anti- inflammatory cytokine genes were associated with latent class membership. Self-report measures of pain, fatigue, sleep disturbance, and depression were completed by 168 oncology outpatients and 85 family caregivers (FCs). Using latent class profile analysis (LCPA), three relatively distinct classes were identified: those who reported low depression and low pain (83%), those who reported high depression and low pain (4.7%), and those who reported high levels of all four symptoms (12.3%). The minor allele of IL4 rs2243248 was associated with membership in the "All high" class along with younger age, being White, being a patient (versus a FC), having a lower functional status score, and having a higher number of comorbid conditions. Findings suggest that LPCA can be used to differentiate distinct phenotypes based on a symptom cluster associated with sickness behavior. Identification of distinct phenotypes provides new evidence for the role of IL4 in the modulation of a sickness behavior symptom cluster in oncology patients and their FCs.