Rejected

MAPK inhibitor (MAPKi) therapy in melanoma leads to accumulation of tumor-surface PD-L1/2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and down-regulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby promoting T-cell activation. During MAPKi therapy in vivo, melanoma cell-intrinsic ITCH knockdown induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8+ T cells, and accelerated acquired resistance only in immune-competent mice. Conversely, tumor cell-intrinsic ITCH over-expression reduced MAPKi-elicited PD-L1 accumulation, augmented intratumoral cytolytic CD8+ T cells, and suppressed acquired resistance in BrafV600MUT, NrasMUT, or Nf1MUT melanoma and KrasMUT-driven cancers. CD8+ T-cell depletion and tumor cell-intrinsic PD-L1 over-expression nullified the phenotype of ITCH over-expression, thereby supporting an in vivo ITCH-PD-L1-T-cell regulatory axis. Moreover, we identify a small-molecular ITCH activator which suppresses acquired MAPKi-resistance in vivo. Thus, MAPKi-induced PD-L1 accelerates resistance, and a PD-L1-degrading ITCH activator prolongs antitumor response.

The COVID-19 pandemic has challenged the entire globe and the need for a vaccine is supreme. Since many vaccines along with Covishield have been granted emergency use authorization, the evaluation and monitoring of safety are crucial. Covishield was rolled out in Nepal on January 27, 2021. So through this study, we aim to identify the prevalence of Adverse Events Following Immunization in general with the first dose of Covishield vaccine, compare Adverse Events Following Immunization in prior COVID-19 positive cases and Adverse Events Following Immunization in co-morbid individuals.

Acute subdural hematoma (ASDH), which causes midline shift of the brain, rarely arises from a dural arteriovenous fistula (DAVF). Herein, we report the first case of a DAVF manifesting ASDH, which was treated less invasively with endovascular embolization of a drainer of the DAVF and hematoma removal under neuroendoscopy. A 59-year-old man with a sudden onset of headache was transported to our hospital. Left ASDH and intracerebral hematoma in the left occipital lobe were detected. A cerebral angiogram revealed a DAVF fed by the petrosquamous branch of the left middle meningeal artery and jugular branch of the right ascending pharyngeal artery. The shunting point in the lateral tentorial DAVF drains through the internal occipital vein to the superior sagittal sinus. A varix was recognized in the draining vein (Borden type 3, Cognard type 4). The DAVF was embolized with Onyx (Medtronic, Minnesota, USA), and the left ASDH was removed with a small craniotomy under neuroendoscopy. No origin of the left ASDH was apparent in the surgical field. The patient was discharged from the hospital on postoperative day 18. The patient's status was modified Rankin scale 1 on discharge. Our management of combined endovascular treatment and neuroendoscopic hematoma removal may be useful and less invasive for hemorrhagic DAVF.

Reliable clinical signs associated with recent brain injuries in neurologically asymptomatic patients during malignant hypertension crisis are lacking. We aimed to compare the prevalence of brain MRI injuries between fully asymptomatic patients and those with isolated headache.

This study aims to investigate the frequency of musculoskeletal adverse effects in acne vulgaris patients receiving systemic isotretinoin treatment.

Human Parechovirus encephalitis is an uncommon infection. Very few of the cases have been reported in the literature so far. These reports are mainly about neonatal encephalitis, primarily affecting preterm neonates. Parechovirus encephalitis in otherwise healthy pediatric populations is a rare entity. Here, we present two unique pediatric cases secondary to Parechovirus infection, one with hemidystonia and another with acute onset of altered mental status, confusion, and headache.

Chronic pain after inguinal hernia repair is a common complication. This study compared the difference between Desarda repair and Lichtenstein repair for inguinal hernia in chronic groin pain.

 Headache is a common symptom among patients with pituitary tumors, as it is in the general population. The aim of the study was to investigate headache as a symptom in patients with pituitary tumors before and 6 months after endoscopic transsphenoidal surgery (TSS).  This is a prospective observational cohort study.  This study was conducted at university tertiary referral hospital.  A total of 110 adult patients underwent endoscopic TSS for pituitary tumors.  The Migraine Disability Assessment (MIDAS) questionnaire was used before and 6 months after surgery for the assessment of headache. Clinical variables with potential influence on headache were analyzed.  Sixty-eight (62%) patients experienced headaches at least once during the 3 months before surgery. Thirty (27%) patients reported disabling headache before surgery, with younger age being an independent associated factor (  < 0.001). In patients with disabling headache before surgery, the median (interquartile range) MIDAS score improved from 78 (27-168) to 16 (2-145;  = 0.049), headache frequency decreased from 45 (20-81) to 14 (4-35) days (  = 0.009), and headache intensity decreased from 6 (5-8) to 5 (4-7) (  = 0.011) after surgery. In total, 16 of the 30 (53%) patients reported a clinically relevant improvement and five (17%) a clinically relevant worsening. Four (5%) patients developed new disabling headache. No predictor for postoperative improvement of headache was identified.  In this prospective study, the results show that disabling headache improves following endoscopic TSS in a subset of patients with pituitary tumors. However, no predictive factors for improvement could be identified.

Although suppression of intraperitoneal gas insufflation response is possible with a higher dose of opioids, sedatives, and inha- lational agents, delayed emergence and poor clinical recovery are still a matter of concern. Here our primary aim was to assess the quality of recovery and the secondary aim includes postinsufflation response, postoperative pain intensity, total opioid requirement, and looking for adverse effects, if any.