TSC2 regulates tumor susceptibility to TRAIL-mediated T-cell killing by orchestrating mTOR signaling.

Resistance to cancer immunotherapy continues to impair common clinical benefit. Here, we use whole-genome CRISPR-Cas9 knockout data to uncover an important role for Tuberous Sclerosis Complex 2 (TSC2) in determining tumor susceptibility to cytotoxic T lymphocyte (CTL) killing in human melanoma cells. TSC2-depleted tumor cells had disrupted mTOR regulation following CTL attack, which was associated with enhanced cell death. Wild-type tumor cells adapted to CTL attack by shifting their mTOR signaling balance toward increased mTORC2 activity, circumventing apoptosis, and necroptosis. TSC2 ablation strongly augmented tumor cell sensitivity to CTL attack in vitro and in vivo, suggesting one of its functions is to critically protect tumor cells. Mechanistically, TSC2 inactivation caused elevation of TRAIL receptor expression, cooperating with mTORC1-S6 signaling to induce tumor cell death. Clinically, we found a negative correlation between TSC2 expression and TRAIL signaling in TCGA patient cohorts. Moreover, a lower TSC2 immune response signature was observed in melanomas from patients responding to immune checkpoint blockade. Our study uncovers a pivotal role for TSC2 in the cancer immune response by governing crosstalk between TSC2-mTOR and TRAIL signaling, aiding future therapeutic exploration of this pathway in immuno-oncology.

Si/Ge interfacial thermal conductance enhancement through Sn nanoparticle embedding.

The improvement of interfacial thermal conductance (ITC) is a crucial aspect of the thermal management of nanodevices. In this paper, the effect of embedding Sn nanoparticles at the Si/Ge interface on ITC was investigated using non-equilibrium molecular dynamics (NEMD) simulations. It was found that although Sn has a higher atomic weight than both silicon and germanium, the ITC can be enhanced by 1.95 times when the nanoparticles reach a suitable number and diameter. The phonon transmission functions and density of states clearly indicate that an increased ITC can be attributed to the enhanced inelastic phonon scattering facilitated by Sn nanoparticles. This enhancement opens up novel channels for interfacial phonon transport. However, when the number of nanoparticles surpasses a suitable value, elastic phonons begin to dominate heat transport, leading to a subsequent decrease in the ITC. Sensitivity analysis further underscores that the ITC exhibits greater responsiveness to changes in diameter. In addition, it is also shown that with increasing temperature, a higher frequency phonon excitation occurs, increasing phonon inelastic scattering and interface transmission. These findings offer a novel strategy for enhancing ITC and deepening our comprehension of both elastic and inelastic phonon processes in interfacial phonon transport.

Shoulder Injury Related to Vaccine Administration (SIRVA) in 16 Patients Following COVID-19 Vaccination Who Presented to Chiropractic, Orthopedic, and Physiotherapy Clinics in Hong Kong During 2021.

BACKGROUND Shoulder injury related to vaccine administration (SIRVA) occurs when an intramuscular deltoid injection is administered into the shoulder joint. This observational study describes clinical features in 16 patients with SIRVA following Coronavirus 2019 (COVID-19) vaccination who presented to chiropractic, orthopedic, and physiotherapy clinics in Hong Kong between January 1, 2021, and January 1, 2022. MATERIAL AND METHODS Adults age ≥18 with new-onset shoulder pain and imaging-confirmed shoulder pathology were retrospectively identified from 35 clinics. Patient demographics and clinical and vaccination details were extracted from the electronic medical record. Shoulder injury was determined by correlating clinical and imaging features. RESULTS Of 730 patients with shoulder pain, 16 SIRVA cases (mean age, 49±10 years, 75% female) were identified; (12/16, 75%) of patients received the Pfizer-BioNTech vaccine while (4/16, 25%) received Sinovac-CoronaVac. The most common diagnosis was adhesive capsulitis (10/16, 63%), followed by bursitis (3/16, 19%) and supraspinatus tear (3/16, 19%). Mean symptom onset was 3.5±2.5 days post-vaccination, and always occurred after the 2nd or 3rd vaccination, involving reduced shoulder range of motion (ROM). Mean baseline pain was 8.1±1 (out of 10). All patients received conservative care (eg, exercise, manual therapies). At 3-month follow-up, mean pain reduced to 2.4±1.4; all patients had normal shoulder ROM. CONCLUSIONS In the past 2 years, millions of intramuscular COVID-19 vaccinations have been administered. It is important that clinicians are aware of SIRVA as a cause of new symptoms of shoulder injury and should ask the patient about recent vaccinations, including for COVID-19.

Prevalence of Serious Pathology Among Adults with Low Back Pain Presenting for Chiropractic Care: A Retrospective Chart Review of Integrated Clinics in Hong Kong.

BACKGROUND There is a limited understanding of the frequency at which chiropractors encounter patients with serious pathology such as malignancy, fracture, and infection. This retrospective study aimed to estimate the prevalence and types of serious pathology among adults with new low back pain presenting to chiropractors in an integrated healthcare organization in Hong Kong, with the hypothesis that such pathology would be found in less than 5% of patients. MATERIAL AND METHODS We identified adults presenting to a chiropractor with new low back pain across 30 clinics with 38 chiropractors, and a subset with previously undiagnosed serious pathology from January 2020 through July 2022. Data were extracted from the electronic medical records, including messaging alerts for serious pathology, notes, radiology reports, and specialist follow-up. Descriptive statistics were utilized to analyze results. RESULTS Among the 7221 identified patients with new-onset low back pain (mean age 61.6±14.3), 35 presented with serious pathology. After excluding 54 cases not meeting inclusion criteria, the prevalence of serious pathology (95% CI) was 35/7221 (0.48%; 0.35-0.67%). Individual condition prevalence included metastasis (0.25%; 0.16-0.39%), fracture (0.12%; 0.07-0.24%), infection (0.04%; 0.01-0.12%), vascular pathology (0.03%; 0.01-0.10%), primary tumor (0.03%; 0.01-0.10%), and gastrointestinal emergency (0.01%; 0.00-0.08%). CONCLUSIONS This study found that serious pathology was uncommon among adults with new low back pain presenting for chiropractic care in Hong Kong, findings which are most consistent with previous research describing the prevalence of serious pathology among low back pain patients in primary care settings.

Effectiveness of Multimodal Chiropractic Care Featuring Spinal Manipulation for Persistent Spinal Pain Syndrome Following Lumbar Spine Surgery: Retrospective Chart Review of 31 Adults in Hong Kong.

BACKGROUND The term "persistent spinal pain syndrome type 2" (PSPS-2) has been proposed by the International Association for the Study of Pain to replace the term "failed back surgery syndrome". This retrospective study aimed to evaluate effectiveness of multimodal care featuring chiropractic spinal manipulation (CSMT) in 31 adults in Hong Kong with PSPS-2. MATERIAL AND METHODS We identified new adult patients with PSPS-2 receiving CSMT from 2016 to 2018. Demographic and clinical data and baseline/follow-up numeric pain rating scale (NPRS) and Oswestry Disability Index (ODI) scores were extracted. Multiple linear regression was used to examine posttreatment NPRS and ODI reduction, with clinical variables as covariates. RESULTS Of 6589 patients with low back pain, 31 met criteria (mean age 52.2±13.7 years). Surgeries included laminectomy (81%), discectomy (13%), and fusion (6%). Mean baseline NRPS was 6.6±1.9; ODI was 43.8±15.1%. Patients received CSMT (100%), drop technique (81%), passive modalities (65%), soft tissue manipulation (13%), flexion-distraction (13%), and mechanical traction (13%). Mean posttreatment NPRS was 0.6±1.0; ODI was 2.4±3.3%. All patients had a minimum clinically important difference for NPRS (≥2/10) and ODI (≥30%). One year after treatment, 48% maintained improvement, 42% experienced recurrence; in 10%, follow-up was unavailable. Regression analysis identified younger age, shorter symptom duration, and greater baseline NPRS as predictors of NPRS reduction; and greater baseline ODI as a predictor of ODI reduction (all P<0.05). CONCLUSIONS Patients with PSPS-2 improved with multimodal care featuring CSMT, which was more effective in patients with younger age, shorter symptom duration, and higher baseline pain or disability levels.

[Textual research on classical famous prescription Dajianzhong Decoction].

The classical famous prescription Dajianzhong Decoction is recorded in Synopsis of the Golden Chamber written by Zhang Zhongjing in the Eastern Han Dynasty. It has a long history and definite clinical effects, while this prescription has not been manufactured into Chinese patent medicine preparation. We collected many ancient books of traditional Chinese medicine(TCM) by using the method of bibliometrics and got 211 valid data terms which involved 67 ancient books. The history, main treated syndromes, formulation principle, origins and processiong of medicinal materials, and decoction method of Dajianzhong Decoction were analyzed. Despite the different views of various generations of medical experts toward the composition of this prescription, the compatibility ratio of Ginseng Radix et Rhizoma to Zingiberis Rhizoma Recens is constant. Furthermore, we explored the origins of synonyms of Dajianzhong Decoction. On the basis of this study, we hope to gain an insight into the research and development of the compound preparations of Dajianzhong Decoction and provide reference for the heritage and innovation of other classical prescriptions.

Ze-Qi-Tang Formula Induces Granulocytic Myeloid-Derived Suppressor Cell Apoptosis via STAT3/S100A9/Bcl-2/Caspase-3 Signaling to Prolong the Survival of Mice with Orthotopic Lung Cancer.

Non-small-cell lung cancer (NSCLC) remains the most common malignancy with the highest morbidity and mortality worldwide. In our previous study, we found that a classic traditional Chinese medicine (TCM) formula Ze-Qi-Tang (ZQT), which has been used in the treatment of respiratory diseases for thousands of years, could directly inhibit the growth of human NSCLC cells via the p53 signaling pathway. In this study, we explored the immunomodulatory functions of ZQT. We found that ZQT significantly prolonged the survival of orthotopic lung cancer model mice by modulating the tumor microenvironment (TME). ZQT remarkably reduced the number of MDSCs (especially G-MDSCs) and inhibited their immunosuppressive activity by inducing apoptosis in these cells via the STAT3/S100A9/Bcl-2/caspase-3 signaling pathway. When G-MDSCs were depleted, the survival promotion effect of ZQT and its inhibitory effect on lung luminescence signal disappeared in tumor-bearing mice. This is the first study to illustrate the immunomodulatory effect of ZQT in NSCLC and the underlying molecular mechanism.

A11, a novel diaryl acylhydrazone derivative, exerts neuroprotection against ischemic injury in vitro and in vivo.

There is an urgent need to develop effective therapies for ischemic stroke, but the complicated pathological processes after ischemia make doing so difficult. In the current study, we identified a novel diaryl acylhydrazone derivative, A11, which has multiple neuroprotective properties in ischemic stroke models. First, A11 was demonstrated to induce neuroprotection against ischemic injury in a dose-dependent manner (from 0.3 to 3 µM) in three in vitro experimental ischemic stroke models: oxygen glucose deprivation (OGD), hydrogen peroxide, and glutamate-stimulated neuronal cell injury models. Moreover, A11 was able to potently alleviate three critical pathological changes, apoptosis, oxidative stress, and mitochondrial dysfunction, following ischemic insult in neuronal cells. Further analysis revealed that A11 upregulated the phosphorylation levels of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in OGD-exposed neuronal cells, suggesting joint activation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MEK)/ERK pathways. In rats with middle cerebral artery occlusion, single-dose administration of A11 (3 mg/kg per day, i.v.) at the onset of reperfusion significantly reduced the infarct volumes and ameliorated neurological deficits. Our study, for the first time, reports the anti-ischemic effect of diaryl acylhydrazone chemical entities, especially A11, which acts on multiple ischemia-associated pathological processes. Our results may provide new clues for the development of an effective therapeutic agent for ischemic stroke.

JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism.

JMJD5, a Jumonji C domain-containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxia-induced cell proliferation. JMJD5 interacts directly with pyruvate kinase muscle isozyme (PKM)2 to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes hypoxia-inducible factor (HIF)-1α-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1α, is recruited to the hypoxia response element site in the lactate dehydrogenase A and PKM2 loci and mediates the recruitment of the latter two proteins. Our data uncover a mechanism whereby PKM2 can be regulated by factor-binding-induced homo/heterooligomeric restructuring, paving the way to cell metabolic reprogram.

The Importance of Early Detection of Spinal Tumors Through Magnetic Resonance Imaging in Chiropractic Practices.

Primary spinal tumors such as schwannomas are uncommon causes of back pain that can be easily missed during the initial workup. Delayed diagnosis is associated with further neurological impairment. A 46-year-old man presented with a six-month history of progressive lower back pain and left leg radiculopathy. Previous treatments failed, including medications, physical therapy, acupuncture, and chiropractic manipulations. Examination revealed weakness (4/5) in left knee extension and ankle dorsiflexion. Magnetic resonance imaging (MRI) revealed a 2-cm intraspinal schwannoma at the L4 level with nerve root compression. The patient underwent laminectomy and gross total resection without any complications. The patient had near-complete symptomatic resolution six weeks postoperatively and returned to normal functioning. After four months of postoperative rehabilitation, the patient remained asymptomatic. This case reinforces the urgent need for early MRI in the presence of neurological deficits and other symptoms, despite normal radiographs. An increased suspicion of spinal tumors can prevent delays in diagnosis and minimize adverse outcomes. Multidisciplinary care optimizes the treatment of complex cases.

Dystonic Tremor as an Atypical Presentation of Cervical Radiculopathy.

Cervical radiculopathy often presents with neck pain, sensory disturbances, or motor weakness. This case report describes an atypical presentation of cervical radiculopathy manifesting as dystonic tremor and brachialgia, which has been documented only once previously. A 46-year-old, right-handed, male delivery worker presented with severe neck pain that gradually evolved into a dystonic tremor and sharp aching pain across his right shoulder. Despite medical intervention, his symptoms persisted, leading him to seek chiropractic care. Physical examination and diagnostic tests revealed degenerative osteophytes, causing bilateral foraminal impingement and narrowing. As orthopedic interventions only provide temporary relief, the patient opted for conservative chiropractic management, which led to a remarkable reduction in pain and complete resolution of the dystonic tremor and brachialgia. This case demonstrates that cervical disc prolapse may manifest with dystonic tremor due to excruciating radiculopathy. Additionally, it emphasizes the potential benefits of chiropractic care in managing such atypical presentations and underscores the need for further research on the mechanisms and management of such cases.

Metastatic Breast Cancer Presenting As Neck Pain in a Pregnant Patient.

Breast cancer metastasizing to the spine during pregnancy is a rare occurrence. A 36-year-old woman experienced persistent neck pain during the third trimester of pregnancy. The pain continued until the postpartum period, severely affecting quality of life (QOL). Physical examination revealed a restricted cervical range of motion. Spinal lesions were detected on magnetic resonance imaging. Metastatic breast cancer was confirmed through a biopsy. The patient underwent radiation therapy for spinal metastasis, chemotherapy for breast cancer, and nonsteroidal anti-inflammatory drug therapy for pain. She was referred for chiropractic care and physical rehabilitation. After six weeks of collaborative treatment, the patient experienced significant pain relief and improvement in strength, mobility, and QOL. This case report highlights the need to evaluate unexplained symptoms in pregnant and postpartum women to exclude sinister pathologies. It demonstrates the need for a multidisciplinary approach that combines oncological, chiropractic, and rehabilitative care to optimize the outcomes in patients with complex presentations.

Chiropractic Management of Lumbar Disc Herniation in a Patient With Co-existing Liver Cancer: A Case Report.

The current case report outlines the chiropractic management of a 30-year-old male construction worker who presented with symptoms of lumbar disc herniation with co-existing stage IV liver cancer. The patient reported experiencing substantial lower back pain and decreased sensation in his right leg following a fall at work, impacting his mobility and quality of life. The complexity of this case is underscored by the challenge of differentiating between pain due to metastatic disease and that related to the fall. The chiropractic treatment plan included gentle joint mobilization, instrument-assisted soft tissue mobilization, and low-impact exercises tailored to the patient's overall health status. The treatment protocol markedly improved pain levels, range of motion, and overall quality of life. This case highlights the potential role of chiropractic care in managing complex cases of lumbar disc herniation, even in the presence of severe illnesses such as liver cancer. This study provides valuable insights into the importance of personalized and adaptable treatment strategies in managing such cases, contributing a unique perspective to the scientific literature.

Conservative Management of Trigeminal Neuralgia and Degenerative Cervical Myelopathy: A Case Report.

It is hypothesized that degenerative cervical myelopathy (DCM) may induce or exacerbate trigeminal neuralgia (TN) through mechanisms such as direct compression of the spinal trigeminal tract, inflammation, or vascular issues, leading to ischemia within cervical segments C3-C4, where the spinal trigeminal nucleus extends. Here, we report the potential therapeutic impact of chiropractic treatment in a 55-year-old female with TN resistance to medical therapy and DCM. The patient received targeted chiropractic care, consisting of high-velocity, low-amplitude (HVLA) spinal manipulation of the C3-C7 and T1-T4 vertebral segments to address joint dysfunction, coupled with intermittent mechanical cervical traction for 20-minute sessions, and focused radial shockwave therapy aimed at myofascial trigger points within the trapezius and levator scapulae muscles. After initiating the chiropractic care plan, the patient experienced a significant reduction in the frequency and severity of TN pain, which persisted throughout the treatment period. Notably, this alleviation in symptoms was maintained at the six-month follow-up, suggesting a sustained therapeutic effect rather than a transient improvement. The lasting nature of the pain reduction provides a compelling argument for the long-term benefits of chiropractic intervention in the management of TN, particularly in cases with concurrent DCM.

Multimodal Management of Coexisting Atlantoaxial Subluxation and Spinal Stenosis in an Older Adult: A Case Report and Literature Review.

This case report investigates the diagnostic and therapeutic challenges caused by the coexistence of atlantoaxial subluxation and spinal stenosis in a 70-year-old male patient with chronic progressive numbness in both hands. A detailed assessment showed that the patient's symptoms were primarily caused by spinal stenosis, not atlantoaxial subluxation. Considering the patient's age and preference for nonsurgical treatment, a conservative chiropractic care plan was implemented, significantly improving his symptoms and quality of life. This case highlights the potential benefit of conservative chiropractic care in managing such complex cases, emphasizes the need for meticulous diagnosis, and requires further research to validate these findings and develop comprehensive management guidelines.

Exploring Chiropractic Healthcare in Hong Kong: Sick Leave Certification Dilemma.

Objective This study aims to investigate the characteristics of chiropractic patients in Hong Kong, their experiences with chiropractic care, and their perspectives on chiropractors' authority over sick leave certificates. Method A cross-sectional survey was conducted among individuals receiving chiropractic treatment in Hong Kong. Data were collected through an online survey from May 11 to August 8, 2023, and descriptive analysis was employed to examine patient demographics, treatment effectiveness, and views on chiropractic sick leave authorization. A total of 522 valid responses were received. Result Among respondents, back pain was the primary reason for seeking chiropractic care, with many experiencing rapid relief and high satisfaction. However, many patients initially consulted other healthcare professionals, indicating potential integration challenges. Lengthy orthopedic wait times in Hong Kong highlight the need for chiropractic care. Concerns arose over chiropractors' inability to issue sick leave certificates, impacting patient convenience, treatment effectiveness, finances, and emotional well-being. Allowing chiropractors to authorize sick leave, with proper regulation, could address these issues. Conclusion In conclusion, this study underscores chiropractic care's potential in Hong Kong's healthcare system and suggests that recognizing chiropractors' role in sick leave authorization can enhance comprehensive patient care.

Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness.

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.

Remission of cervicogenic dysphagia associated with biomechanical dysfunction following chiropractic therapy.

Cervicogenic dysphagia is a complex condition that can arise from biomechanical dysfunction in the cervical spine. Conventional treatment outcomes are not always guaranteed. Chiropractic treatment is considered an alternative treatment for dysphagia, yet there is a lack of evidence supporting its effectiveness. We present the case of a 48-year-old male who had difficulty swallowing for eight months. He had a feeling of food stuck in his throat when eating hard food but without any pain when swallowing, and eventually, he could not swallow any dry food. He was diagnosed with dysphagia associated with an anxiety disorder and was treated with medication, but there was no improvement in his condition. A full-spine radiograph revealed biomechanical dysfunction, including reduced cervical lordosis and levoscoliosis of the upper thoracic spine. After nine months of conventional physiotherapy, the patient completely recovered from his symptoms, with significantly improved biomechanical parameters. This study highlights the potential mechanism of cervicogenic dysphagia and the effect of chiropractic treatment in managing it. Applying chiropractic treatment, including spinal manipulative therapy, instrument-assisted soft tissue manipulation, and mechanical traction, might bring a positive outcome for dysphagia patients with careful consideration.

Dorsal Scapular Osteochondroma in the Chiropractic Clinic: A Case Report and Literature Review.

Osteochondromas are benign bone tumors that occur only rarely in the scapula. We report a case of an eight-year-old boy with dorsal scapular osteochondroma that initially presented as middle back pain, scoliosis, and a winged scapula. Unlike in most reported cases, the patient did not report severe pain. The chiropractor reviewed his previous radiograph and ordered a computed tomography scan, which revealed a bony mass on the dorsal aspect of the left scapula consistent with an osteochondroma. Given the patient's age and lack of symptoms, a conservative chiropractic treatment plan, focusing on posture, flexibility, and close monitoring, was adopted. Scapular mobilization, spinal adjustment, and a tailored exercise program provided symptomatic relief from scoliosis and improved mobility. Follow-up evaluations revealed further enlargement of the osteochondroma without accompanying symptoms. This study highlights the importance of considering a broad range of differential diagnoses in pediatric patients with atypical or unclear presentations. This study also demonstrates the potential benefits of conservative chiropractic management in patients with osteochondroma-induced musculoskeletal issues.

Non-surgical Restoration of L3/L4 Disc Herniation.

We report the case of a 52-year-old Asian man presenting with severe lower back pain and bilateral radiculopathy due to acute L3/L4 disc extrusion, causing severe spinal canal stenosis and bilateral L4 nerve root compression. Following a ten-week conservative management plan consisting of high-velocity, low-amplitude spinal manipulation, adjunctive therapies, and home exercise, the patient experienced significant pain relief, functional improvement, and near resolution of deficits. A six-month follow-up MRI revealed the resolution of the L3/L4 disc extrusion, and the patient remained asymptomatic at nine months. This case highlights the potential for spontaneous resorption of a lumbar disc herniation and symptomatic improvement with conservative management, including chiropractic treatment. A favorable natural course of a disc herniation should be considered when deciding between early surgical intervention and conservative management, warranting further prospective studies to evaluate the effectiveness of chiropractic treatment and the role of spontaneous regression in symptomatic lumbar disc herniation.